Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

[1]  F. McCormick,et al.  Mutation Analysis of BRAF, MEK1 and MEK2 in 15 Ovarian Cancer Cell Lines: Implications for Therapy , 2007, PloS one.

[2]  Kwok-Kin Wong,et al.  Differences underlying EGFR and HER2 oncogene addiction , 2010, Cell cycle.

[3]  Jan-Gowth Chang,et al.  Mutation Analysis of the Putative Tumor Suppressor Gene PTEN/MMAC1 in Hepatocellular Carcinoma , 2000, Cancer investigation.

[4]  A. Weiss,et al.  Induction of NF-κB by the Akt/PKB kinase , 1999, Current Biology.

[5]  M. Huber,et al.  The role of SHIP in cytokine-induced signaling. , 2003, Reviews of physiology, biochemistry and pharmacology.

[6]  A. Erol.  Genotoxic stress-mediated cell cycle activities for the decision of cellular fate , 2011, Cell cycle.

[7]  A. Osunkoya,et al.  Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. , 2008, Cancer research.

[8]  P. Majerus,et al.  The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Volker Brinkmann,et al.  Prohibitin is required for Ras-induced Raf–MEK–ERK activation and epithelial cell migration , 2005, Nature Cell Biology.

[10]  Yukiko Nakamura,et al.  Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor , 2011, Aging.

[11]  L. Rohrschneider,et al.  p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity. , 1996, Genes & development.

[12]  W. Kolch,et al.  Negative regulation of Raf-1 by phosphorylation of serine 621 , 1996, Molecular and cellular biology.

[13]  G. Mills,et al.  A novel AKT3 mutation in melanoma tumours and cell lines , 2008, British Journal of Cancer.

[14]  S. Erceg,et al.  FM19G11: A new modulator of HIF that links mTOR activation with the DNA damage checkpoint pathways , 2010, Cell cycle.

[15]  V. Anisimov,et al.  Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo , 2010, Cell cycle.

[16]  L. Shaw,et al.  Integrin (α6β4) regulation of eIF-4E activity and VEGF translation , 2002, The Journal of Cell Biology.

[17]  M. Minden,et al.  Constitutive phosphorylation of the S6 ribosomal protein via mTOR and ERK signaling in the peripheral blasts of acute leukemia patients. , 2006, Experimental hematology.

[18]  T. Schug.  mTOR favors senescence over quiescence in p53-arrested cells , 2010, Aging.

[19]  L. Zeng,et al.  Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): A double-edged sword? , 2010, Cell cycle.

[20]  A. Mobasheri,et al.  Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes. , 2005, Histology and histopathology.

[21]  Kevin A. Janes,et al.  RUNX1 and its understudied role in breast cancer , 2011, Cell cycle.

[22]  D. Dinh,et al.  Cord blood stem cells revert glioma stem cell EMT by down regulating transcriptional activation of Sox2 and Twist1 , 2011, Oncotarget.

[23]  F. Couch,et al.  17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K, and SIGma1B genes. , 2000, Cancer research.

[24]  M. Diaz-Meco,et al.  The Par-4/PTEN connection in tumor suppression , 2009, Cell cycle.

[25]  B. Hemmings,et al.  Advances in protein kinase B signalling: AKTion on multiple fronts. , 2004, Trends in biochemical sciences.

[26]  Stephen L. Abrams,et al.  Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy. , 2010, Cell cycle.

[27]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

[28]  D. Spandidos,et al.  Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (review). , 2011, International journal of oncology.

[29]  Mikhail V. Blagosklonny,et al.  Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives , 2010, Aging.

[30]  A. Nakashima,et al.  Specific Activation of mTORC1 by Rheb G-protein in Vitro Involves Enhanced Recruitment of Its Substrate Protein* , 2009, Journal of Biological Chemistry.

[31]  C. Payne,et al.  Rapamycin increases oxidative stress response gene expression in adult stem cells , 2012, Aging.

[32]  Philippe P Roux,et al.  mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide , 2010, The EMBO journal.

[33]  J. Lippincott-Schwartz,et al.  Starved cells use mitochondria for autophagosome biogenesis , 2010, Cell cycle.

[34]  Shuang Huang,et al.  Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. , 2009, Cancer research.

[35]  C. Nucera,et al.  The BRAFV600E mutation: what is it really orchestrating in thyroid cancer? , 2010, Oncotarget.

[36]  O. Stoeltzing,et al.  Implication of RICTOR in the mTOR inhibitor-mediated induction of insulin-like growth factor-I receptor (IGF-IR) and human epidermal growth factor receptor-2 (Her2) expression in gastrointestinal cancer cells. , 2010, Biochimica et biophysica acta.

[37]  U. Weidle,et al.  Synthetic lethality-based targets for discovery of new cancer therapeutics. , 2011, Cancer genomics & proteomics.

[38]  J. McCubrey,et al.  Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia , 2012, Leukemia.

[39]  Sreenath V. Sharma,et al.  Exploiting the balance between life and death: targeted cancer therapy and "oncogenic shock". , 2010, Biochemical pharmacology.

[40]  D. Peeper,et al.  Epithelial-mesenchymal transition and senescence: two cancer-related processes are crossing paths , 2010, Aging.

[41]  P. Jat,et al.  Deciphering the role of Nuclear Factor-κB in cellular senescence , 2011, Aging.

[42]  G. Fisone,et al.  mTORC1 signaling in Parkinson disease and L-DOPA-induced dyskinesia: A sensitized matter , 2010, Cell cycle.

[43]  T. V. Bykova,et al.  p21Waf1 is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate , 2010, Cell cycle.

[44]  G. Frühbeck,et al.  Aquaglyceroporins serve as metabolic gateways in adiposity and insulin resistance control , 2011, Cell cycle.

[45]  A. Pinchera,et al.  BRAFV599E Mutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas , 2004 .

[46]  G. Gurtner,et al.  HIF-1α dysfunction in diabetes , 2010 .

[47]  Sean E. Egan,et al.  Elevated PI3K signaling drives multiple Breast Cancer subtypes , 2011, Oncotarget.

[48]  R. Eeles,et al.  Molecular markers for predicting prostate cancer stage and survival , 2000, BJU international.

[49]  B. Groner,et al.  Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. , 1997, Immunity.

[50]  Hong Wu,et al.  Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Su-Jin Lee,et al.  Slug, mammalian homologue gene of Drosophila escargot, promotes neuronal-differentiation through suppression of HEB/daughterless , 2010, Cell cycle.

[52]  F. Motoi,et al.  Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. , 2003, The American journal of pathology.

[53]  Laura Tolosi,et al.  Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. , 2009, The Journal of clinical investigation.

[54]  Mariano Provencio,et al.  Promoter methylation of the PTEN gene is a common molecular change in breast cancer , 2004, Genes, chromosomes & cancer.

[55]  K. Valerie,et al.  ATM-dependent ERK signaling via AKT in response to DNA double-strand breaks , 2011, Cell cycle.

[56]  S J Cook,et al.  Mechanisms of acquired resistance to ERK1/2 pathway inhibitors , 2013, Oncogene.

[57]  T. Mak,et al.  Portrait of PTEN: Messages from mutant mice , 2008, Cancer science.

[58]  Patricia A. Kruk,et al.  MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN (Cancer Research (2008) 68, (425-433)) , 2008 .

[59]  D. Morrison,et al.  KSR regulation of the Raf-MEK-ERK cascade. , 2006, Methods in enzymology.

[60]  E. Ranheim,et al.  Distinct requirements of hematopoietic stem cell activity and Nras G12D signaling in different cell types during leukemogenesis , 2011, Cell cycle.

[61]  G. Mayr,et al.  Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations , 2007, Gene Therapy.

[62]  G. Batist,et al.  The EphB2 tumor suppressor induces autophagic cell death via concomitant activation of the ERK1/2 and PI3K pathways , 2010, Cell cycle.

[63]  D. Sabatini,et al.  DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival , 2009, Cell.

[64]  Stephen L. Abrams,et al.  Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways , 2011, Journal of cellular physiology.

[65]  R. Shaw,et al.  The LKB1–AMPK pathway: metabolism and growth control in tumour suppression , 2009, Nature Reviews Cancer.

[66]  M. Blagosklonny.  Calorie restriction: Decelerating mTOR-driven aging from cells to organisms (including humans) , 2010, Cell cycle.

[67]  F. Sotgia,et al.  HIF1-alpha functions as a tumor promoter in cancer-associated fibroblasts, and as a tumor suppressor in breast cancer cells , 2010, Cell cycle.

[68]  D. Gutmann,et al.  Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially and Temporally Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth , 2011, Journal of neuropathology and experimental neurology.

[69]  E. Jacinto,et al.  mTOR complex 2 signaling and functions , 2011, Cell cycle.

[70]  A. Tsirigos,et al.  Ketones and lactate “fuel” tumor growth and metastasis , 2010, Cell cycle.

[71]  M. Cosma,et al.  Somatic cell reprogramming control: Signaling pathway modulation versus transcription factor activities , 2009, Cell cycle.

[72]  Govind Bhagat,et al.  Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia , 2007, Nature Medicine.

[73]  Bing-Hua Jiang,et al.  Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. , 2006, Cellular signalling.

[74]  G. Pani.  From growing to secreting: New roles for mTOR in aging cells , 2011, Cell cycle.

[75]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[76]  B. Martín-Castillo,et al.  Metformin activates an Ataxia Telangiectasia Mutated (ATM)/Chk2-regulated DNA damage-like response , 2011, Cell cycle.

[77]  Tom Misteli,et al.  Ubiquitination Regulates PTEN Nuclear Import and Tumor Suppression , 2007, Cell.

[78]  M. Blagosklonny,et al.  The purpose of the HIF-1/PHD feedback loop: To limit mTOR-induced HIF-1α , 2011, Cell cycle.

[79]  W. Lee,et al.  Regulation of Phosphorylation of Thr-308 of Akt, Cell Proliferation, and Survival by the B55α Regulatory Subunit Targeting of the Protein Phosphatase 2A Holoenzyme to Akt* , 2008, Journal of Biological Chemistry.

[80]  Steven Whittaker,et al.  Gatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies , 2010, Science Translational Medicine.

[81]  Jie Zhou,et al.  Autophagy in cancer associated fibroblasts promotes tumor cell survival , 2010, Cell cycle.

[82]  K. Mori,et al.  XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. , 2004, The Journal of cell biology.

[83]  N. Girard,et al.  New driver mutations in non-small-cell lung cancer. , 2011, The Lancet. Oncology.

[84]  Richard Wooster,et al.  BRAF and RAS mutations in human lung cancer and melanoma. , 2002, Cancer research.

[85]  M. Maiuri,et al.  Neuroendocrine regulation of autophagy by leptin , 2011, Cell cycle.

[86]  Hui Liu,et al.  mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes , 2010, Cell cycle.

[87]  V. Hu.  The Cell Cycle , 1994, GWUMC Department of Biochemistry Annual Spring Symposia.

[88]  M. Vidal,et al.  TACC3-TSC2 maintains nuclear envelope structure and controls cell division , 2010, Cell cycle.

[89]  M. Hengstschläger,et al.  Tuberin and PRAS40 are anti-apoptotic gatekeepers during early human amniotic fluid stem-cell differentiation. , 2012, Human molecular genetics.

[90]  J. Blenis,et al.  ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions , 2004, Microbiology and Molecular Biology Reviews.

[91]  L. Shaw,et al.  Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. , 2002, The Journal of cell biology.

[92]  J. Nickels,et al.  PP2ACdc55 is required for multiple events during meiosis I , 2011, Cell cycle.

[93]  E. Muraille,et al.  Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells. , 1999, The Biochemical journal.

[94]  E. Zacksenhaus,et al.  Multiple pathways counteract cell death induced by RB1 loss: Implications for cancer , 2011, Cell cycle.

[95]  Stephen L. Abrams,et al.  Involvement of Akt-1 and mTOR in Sensitivity of Breast Cancer to Targeted Therapy , 2011, Oncotarget.

[96]  William Pao,et al.  Genetic predictors of MEK dependence in non-small cell lung cancer. , 2008, Cancer research.

[97]  Hongyu Zhou,et al.  Role of mTOR signaling in tumor cell motility, invasion and metastasis. , 2011, Current protein & peptide science.

[98]  C. Cordon-Cardo,et al.  Overexpression of cyclin D1 is associated with metastatic prostate cancer to bone. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[99]  Joe W. Gray,et al.  PIK3CA is implicated as an oncogene in ovarian cancer , 1999, Nature Genetics.

[100]  O. Kepp,et al.  Defective autophagy associated with LC3 puncta in epothilone-resistant cancer cells , 2010, Cell cycle.

[101]  J. P. D. Magalhães.  A role for Ras signaling in modulating mammalian aging by the GH/IGF1 axis. , 2011 .

[102]  Deborah H. Anderson.  p85 plays a critical role in controlling flux through the PI3K/PTEN signaling axis through dual regulation of both p110 (PI3K) and PTEN , 2010, Cell Cycle.

[103]  F. Sotgia,et al.  Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis , 2011, Cell cycle.

[104]  S. Berberich,et al.  HdmX overexpression inhibits oncogene induced cellular senescence , 2010, Cell cycle.

[105]  Danish Sayed,et al.  AKT-ing via microRNA , 2010, Cell cycle.

[106]  S. Ambs,et al.  Candidate pathways linking inducible nitric oxide synthase to a basal-like transcription pattern and tumor progression in human breast cancer , 2011, Cell cycle.

[107]  R. DePinho,et al.  The LKB1 tumor suppressor negatively regulates mTOR signaling. , 2004, Cancer cell.

[108]  B. Johansson,et al.  BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias , 2008, Leukemia.

[109]  J. Boyd,et al.  Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. , 1997, Cancer research.

[110]  Aristotelis Tsirigos,et al.  The autophagic tumor stroma model of cancer , 2010, Cell cycle.

[111]  Baljit Singh,et al.  Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus , 1998, Genes, chromosomes & cancer.

[112]  J. Woodgett,et al.  Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. , 1991, European journal of biochemistry.

[113]  P. Crespo,et al.  Mxi2 promotes stimulus‐independent ERK nuclear translocation , 2007, The EMBO journal.

[114]  F. Khanim,et al.  Slug Regulates Integrin Expression and Cell Proliferation in Human Epidermal Keratinocytes* , 2006, Journal of Biological Chemistry.

[115]  E. Felip,et al.  Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer , 2011, Oncotarget.

[116]  Paul Ellis,et al.  PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer , 2010, Proceedings of the National Academy of Sciences.

[117]  M. Blagosklonny.  Progeria, rapamycin and normal aging: recent breakthrough , 2011, Aging.

[118]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[119]  A. Newton,et al.  PHLiPPing the switch on Akt and protein kinase C signaling , 2008, Trends in Endocrinology & Metabolism.

[120]  L. Beretta,et al.  Activation of the N-Ras–PI3K–Akt-mTOR Pathway by Hepatitis C Virus: Control of Cell Survival and Viral Replication , 2005, Journal of Virology.

[121]  M. Konopleva,et al.  Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia , 2005, Leukemia.

[122]  S. Baker,et al.  PTEN and the PI3-kinase pathway in cancer. , 2009, Annual review of pathology.

[123]  J. Cheng,et al.  Role of p53 up-regulated modulator of apoptosis and phosphorylated Akt in melanoma cell growth, apoptosis, and patient survival. , 2006, Cancer research.

[124]  Stephen L. Abrams,et al.  Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells , 2011, Cell cycle.

[125]  C. Rongo.  Epidermal growth factor and aging: A signaling molecule reveals a new eye opening function , 2011, Aging.

[126]  J. Cheng,et al.  AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[127]  Michael E. Greenberg,et al.  Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase , 1996, Science.

[128]  J. Barata,et al.  PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. , 2008, The Journal of clinical investigation.

[129]  L. Mahimainathan,et al.  Inactivation of Platelet-derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase* , 2004, Journal of Biological Chemistry.

[130]  Sheng-Nan Lu,et al.  Down-regulation of tumor suppressor gene PTEN, overexpression of p53, plus high proliferating cell nuclear antigen index predict poor patient outcome of hepatocellular carcinoma after resection. , 2007, Oncology reports.

[131]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[132]  M. Blagosklonny.  Why the disposable soma theory cannot explain why women live longer and why we age , 2010, Aging.

[133]  T. Cloughesy,et al.  AMPK: A metabolic checkpoint that regulates the growth of EGFR activated glioblastomas , 2010, Cell cycle.

[134]  T. C. Woods.  Regulation of cell migration by mTOR is mediated through changes in p27Kip1 phosphorylation , 2010, Cell cycle.

[135]  H. Do,et al.  Rarity of AKT1 and AKT3 E17K mutations in squamous cell carcinoma of lung , 2010, Cell cycle.

[136]  Anna-Pavlina G. Haramis,et al.  Insights from model organisms on the functions of the tumor suppressor protein LKB1: Zebrafish chips in , 2011, Aging.

[137]  M. Iorio,et al.  HER2 signaling enhances 5′UTR‐mediated translation of c‐Myc mRNA , 2004, Journal of cellular physiology.

[138]  Ziqiu Wang,et al.  Phosphorylation regulates Myc expression via prolonged activation of the mitogen‐activated protein kinase pathway , 2006, Journal of cellular physiology.

[139]  J. Tamburini,et al.  Targeting translation in acute myeloid leukemia: A new paradigm for therapy? , 2009, Cell cycle.

[140]  D. Stokoe,et al.  5′ Phospholipid Phosphatase SHIP-2 Causes Protein Kinase B Inactivation and Cell Cycle Arrest in Glioblastoma Cells , 2000, Molecular and Cellular Biology.

[141]  M. Emi,et al.  PTEN/MMAC1 Mutations in Hepatocellular Carcinomas: Somatic Inactivation of Both Alleles in Tumors , 1999, Japanese journal of cancer research : Gann.

[142]  L. Neckers,et al.  Hsp90 phosphorylation, Wee1 and the cell cycle , 2010, Cell cycle.

[143]  C. Bonifer,et al.  Repeat element-driven activation of proto-oncogenes in human malignancies , 2010, Cell cycle.

[144]  T. McGraw,et al.  The Akt kinases: Isoform specificity in metabolism and cancer , 2009, Cell cycle.

[145]  R. Prywes,et al.  ATF1 Phosphorylation by the ERK MAPK Pathway Is Required for Epidermal Growth Factor-induced c-jun Expression* , 2002, The Journal of Biological Chemistry.

[146]  D. Mandelker,et al.  Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110α/p85α , 2008, Cell cycle.

[147]  J. McCubrey,et al.  Targeted therapy for hepatocellular carcinoma: novel agents on the horizon , 2012, Oncotarget.

[148]  Yu Jiang.  mTOR goes to the nucleus , 2010, Cell cycle.

[149]  B. Bonavida,et al.  Mechanisms of nitric oxide-mediated inhibition of EMT in cancer , 2010, Cell cycle.

[150]  B. Martín-Castillo,et al.  Metformin against TGFβ-induced epithelial-to-mesenchymal transition (EMT): From cancer stem cells to aging-associated fibrosis , 2010, Cell cycle.

[151]  Wei Du,et al.  Targeting Rb Mutant Cancers by Inactivating TSC2 , 2010, Oncotarget.

[152]  Arthur Js.  MSK activation and physiological roles. , 2008 .

[153]  S. Amato,et al.  Bioenergy sensing in the brain , 2011, Cell cycle.

[154]  N. Sonenberg,et al.  eIF4B controls survival and proliferation and is regulated by proto-oncogenic signaling pathways , 2010, Cell cycle.

[155]  Y. Tao,et al.  Chaperones and the maturation of steroid hormone receptor complexes , 2011, Oncotarget.

[156]  Konstantinos J. Mavrakis,et al.  Cooperative control of tumor suppressor genes by a network of oncogenic microRNAs , 2011, Cell cycle.

[157]  Donna J. Webb,et al.  FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly , 2004, Nature Cell Biology.

[158]  G. Giaccone,et al.  Targeting the dynamic HSP90 complex in cancer , 2010, Nature Reviews Cancer.

[159]  Muffy Calder,et al.  The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier , 2010, Science Signaling.

[160]  P. Coffer,et al.  The role of the PI3K-PKB signaling module in regulation of hematopoiesis , 2009, Cell cycle.

[161]  D. Adhikari,et al.  mTOR signaling in the control of activation of primordial follicles. , 2010, Cell cycle.

[162]  D. Perrotti,et al.  Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias , 2008, Cancer and Metastasis Reviews.

[163]  M. Butler,et al.  Analysis of PTEN mutations and deletions in B‐cell non‐Hodgkin's lymphomas , 1999, Genes, chromosomes & cancer.

[164]  L. Huang,et al.  Requirement of evading apoptosis for HIF-1α-induced malignant progression in mouse cells , 2011, Cell cycle.

[165]  V. Longo,et al.  Conserved role of Ras-GEFs in promoting aging: from yeast to mice , 2011, Aging.

[166]  Jing Yang,et al.  Targeting invadopodia to block breast cancer metastasis , 2011, Oncotarget.

[167]  G. Browne,et al.  ZEB proteins link cell motility with cell cycle control and cell survival in cancer , 2010, Cell cycle.

[168]  G. Fisone,et al.  HDAC inhibitors conquer polycomb proteins , 2010 .

[169]  A. Simon,et al.  Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia , 2011, Cell cycle.

[170]  M. Hall,et al.  Rapamycin passes the torch: a new generation of mTOR inhibitors , 2011, Nature Reviews Drug Discovery.

[171]  Qingsheng Li,et al.  Fine-tuning CD8+ T-cell functional responses: mTOR acts as a rheostat for regulating CD8+ T-cell proliferation, survival and differentiation? , 2010, Cell cycle.

[172]  Y. Chen,et al.  Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. , 2000, Journal of the National Cancer Institute.

[173]  L. Platanias,et al.  Inhibition of phosphatidylinositol 3'-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway. , 2004, Biochemical and biophysical research communications.

[174]  G. Robert,et al.  Azacitidine-resistant SKM1 myeloid cells are defective for AZA-induced mitochondrial apoptosis and autophagy , 2011, Cell cycle.

[175]  D. Morrison,et al.  Complexity in KSR function revealed by Raf inhibitor and KSR structure studies , 2011, Small GTPases.

[176]  T. Finkel,et al.  Metabolism meets autophagy , 2010, Cell cycle.

[177]  M. Nikiforov,et al.  Pathways of oncogene-induced senescence in human melanocytic cells , 2010, Cell cycle.

[178]  J. Blenis,et al.  ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. , 2010, Molecular cell.

[179]  A. Khwaja,et al.  PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kB, MAPkinase and p53 pathways , 2005, Leukemia.

[180]  M. Blagosklonny,et al.  DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence , 2010, Aging.

[181]  Stephen L. Abrams,et al.  Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging , 2011, Aging.

[182]  K. Knudsen.  A tale of three PKCs , 2011, Cell cycle.

[183]  I. Hanamura,et al.  Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia , 2003, Leukemia.

[184]  Jingwei Cheng,et al.  A functional serine 118 phosphorylation site in estrogen receptor-alpha is required for down-regulation of gene expression by 17beta-estradiol and 4-hydroxytamoxifen. , 2007, Endocrinology.

[185]  Shu-Bing Qian,et al.  mTOR signaling in protein homeostasis , 2011, Cell cycle.

[186]  J. Blenis,et al.  ERK2/Fra1/ZEB pathway induces epithelial-to-mesenchymal transition , 2010, Cell cycle.

[187]  R. DePinho,et al.  The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin , 2005, Science.

[188]  J. Węsierska‐Gądek,et al.  mTOR and its link to the picture of Dorian Gray - re-activation of mTOR promotes aging , 2010, Aging.

[189]  G. Maulucci,et al.  Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage , 2010, Aging.

[190]  L. Porter,et al.  The tumor suppressor tuberin regulates mitotic onset through the cellular localization of cyclin B1 , 2011, Cell cycle.

[191]  J. Asara,et al.  Characterization of Rictor Phosphorylation Sites Reveals Direct Regulation of mTOR Complex 2 by S6K1 , 2009, Molecular and Cellular Biology.

[192]  R. Godschalk,et al.  Adult-onset, short-term dietary restriction reduces cell senescence in mice , 2010, Aging.

[193]  Z. Darżynkiewicz.  Another "Janus paradox" of p53: induction of cell senescence versus quiescence , 2010, Aging.

[194]  E. Jaffe,et al.  PTEN Gene Alterations in Lymphoid Neoplasms , 1998 .

[195]  Ming Zhou,et al.  Regulation of Raf-1 by direct feedback phosphorylation. , 2005, Molecular cell.

[196]  Qing-Yuan Sun.  Ndc80 complex: New evidence for the existence of spindle assembly checkpoint in mammalian oocyte meiosis , 2011, Cell cycle.

[197]  Su-Jeong Kim,et al.  Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway. , 2004, Molecular cancer research : MCR.

[198]  J. Blando,et al.  Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions , 2011, Cell cycle.

[199]  R. DeBiasi,et al.  MEKK1 regulates calpain‐dependent proteolysis of focal adhesion proteins for rear‐end detachment of migrating fibroblasts , 2003, The EMBO journal.

[200]  R. Treisman,et al.  Ternary Complex Factors SAP-1 and Elk-1, but Not Net, Are Functionally Equivalent in Thymocyte Development , 2010, The Journal of Immunology.

[201]  N. Nagasue,et al.  Impact of PTEN expression on the outcome of hepatitis C virus‐positive cirrhotic hepatocellular carcinoma patients: Possible relationship with COX II and inducible nitric oxide synthase , 2002, International journal of cancer.

[202]  R. Parsons,et al.  The role of PTEN signaling perturbations in cancer and in targeted therapy , 2008, Oncogene.

[203]  M. Nagarkatti,et al.  Taming the beast within: resveratrol suppresses colitis and prevents colon cancer , 2010, Aging.

[204]  Jun Qin,et al.  Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. , 2011, Cancer research.

[205]  R. Zamoyska,et al.  How does the mammalian target of rapamycin (mTOR) influence CD8 T-cell differentiation? , 2010, Cell cycle.

[206]  M. Blagosklonny.  The power of chemotherapeutic engineering: Arresting cell cycle and suppressing senescence to protect from mitotic inhibitors , 2011, Cell cycle.

[207]  A. Ferrando,et al.  The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia , 2008, Cell cycle.

[208]  R. DePinho,et al.  BRafV600E cooperates with Pten silencing to elicit metastatic melanoma , 2009, Nature Genetics.

[209]  Chen Zhao,et al.  mTOR pathway activation in age-related retinal disease , 2011, Aging.

[210]  N. Hay,et al.  The two TORCs and Akt. , 2007, Developmental cell.

[211]  J. McCubrey,et al.  Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. , 2008, Current opinion in investigational drugs.

[212]  I. Mellinghoff,et al.  AKT Activity Determines Sensitivity to Mammalian Target of Rapamycin (mTOR) Inhibitors by Regulating Cyclin D1 and c-myc Expression* , 2004, Journal of Biological Chemistry.

[213]  A. Aliaga,et al.  Metformin abolishes increased tumor 18F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet , 2011, Cell cycle.

[214]  R. DePinho,et al.  mTORC1 signaling governs hematopoietic stem cell quiescence , 2009, Cell cycle.

[215]  Jingwei Cheng,et al.  A Functional Serine 118 Phosphorylation Site in Estrogen Receptor-α Is Required for Down-Regulation of Gene Expression by 17β-Estradiol and 4-Hydroxytamoxifen , 2007 .

[216]  A. Richardson,et al.  Reversing the Warburg effect through stromal autophagy , 2011, Cell cycle.

[217]  J. Menéndez,et al.  Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs) , 2011, Cell cycle.

[218]  J. Qin,et al.  Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase. , 2005, Molecular biology of the cell.

[219]  W. Gu,et al.  Targeting the degradation of cyclin D1 will help to eliminate oncogene addiction , 2010, Cell cycle.

[220]  K. Gould,et al.  KSR1 is a functional protein kinase capable of serine autophosphorylation and direct phosphorylation of MEK1. , 2011, Experimental cell research.

[221]  L. Timchenko,et al.  GSK3β and aging liver , 2009, Aging.

[222]  M. Knowles,et al.  Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer , 2009, Cancer and Metastasis Reviews.

[223]  M. Serrano.  Shifting senescence into quiescence by turning up p53 , 2010, Cell cycle.

[224]  A. Newton,et al.  PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. , 2005, Molecular cell.

[225]  Alma L. Burlingame,et al.  A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK , 2011, Nature.

[226]  Trevor J Pugh,et al.  Initial genome sequencing and analysis of multiple myeloma , 2011, Nature.

[227]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[228]  M. Hengstschläger,et al.  mTOR protein localization is cell cycle-regulated , 2011, Cell cycle.

[229]  F. Pallardó,et al.  RasGrf1 deficiency delays aging in mice , 2011, Aging.

[230]  S. Zimmer,et al.  Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. , 2000, Anticancer research.

[231]  U. Rapp,et al.  Regulation of RAF Activity by 14-3-3 Proteins , 2009, Journal of Biological Chemistry.

[232]  A. Basu.  PKCε paves the way for prostate cancer , 2011, Cell Cycle.

[233]  D. Leroith,et al.  Hyperinsulinemia and type 2 diabetes: Impact on cancer , 2010, Cell cycle.

[234]  J. Field,et al.  Oxidation of Akt2 kinase promotes cell migration and regulates G1-S transition in the cell cycle , 2011, Cell cycle.

[235]  A. Hall,et al.  Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia. , 2008, Cancer research.

[236]  S. Zimmer,et al.  Translational control and metastatic progression: Enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs , 2004, Clinical & Experimental Metastasis.

[237]  J. Menéndez,et al.  Polo-like kinase 1 regulates activation of AMP-activated protein kinase (AMPK) at the mitotic apparatus , 2011, Cell cycle.

[238]  Darell D. Bigner,et al.  Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes , 2010, Oncotarget.

[239]  Stephen L. Abrams,et al.  Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs , 2010, Cell cycle.

[240]  R. de Cabo,et al.  Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[241]  K. Aldape,et al.  FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. , 2009, Molecular cell.

[242]  L. Galluzzi,et al.  Hormesis, cell death and aging , 2011, Aging.

[243]  Juan Wu,et al.  Regulation of Akt signaling activation by ubiquitination , 2010, Cell cycle.

[244]  W. Hahn,et al.  Recurrent BRAF mutations in Langerhans cell histiocytosis. , 2010, Blood.

[245]  Yong Zhang,et al.  Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[246]  D. Durocher,et al.  MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks , 2011, Cell cycle.

[247]  F. E. Bertrand,et al.  The complexity of PTEN: mutation, marker and potential target for therapeutic intervention , 2004, Expert opinion on therapeutic targets.

[248]  J. Fuxe,et al.  Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes , 2010, Cell cycle.

[249]  J. Sanders,et al.  The physiology and pathophysiology of rapamycin resistance , 2011, Cell cycle.

[250]  Y. I. Lee,et al.  PTEN modulates hepatitis B virus-X protein induced survival signaling in Chang liver cells. , 2006, Virus research.

[251]  E. Asselin,et al.  Regulation of COX-2 protein expression by Akt in endometrial cancer cells is mediated through NF-κB/IκB pathway , 2004, Molecular Cancer.

[252]  P. Pandolfi,et al.  Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. , 2008, The Journal of clinical investigation.

[253]  Dong-Myung Shin,et al.  RasGrf1: genomic imprinting, VSELs, and aging , 2011, Aging.

[254]  K. Iwai.  Linear polyubiquitin chains , 2011, Cell cycle.

[255]  Weiwei Yang,et al.  Ras-Induced and Extracellular Signal-Regulated Kinase 1 and 2 Phosphorylation-Dependent Isomerization of Protein Tyrosine Phosphatase (PTP)-PEST by PIN1 Promotes FAK Dephosphorylation by PTP-PEST , 2011, Molecular and Cellular Biology.

[256]  C. Simone,et al.  The AMPK-FoxO3A axis as a target for cancer treatment , 2010, Cell cycle.

[257]  Z. Nahlé,et al.  Double trouble: When Sonic hedgehog signaling meets TSC inactivation , 2010, Cell cycle.

[258]  M. Blagosklonny.  Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis , 2010, Aging.

[259]  T. Löning,et al.  PTEN Expression in Breast and Endometrial Cancer: Correlations with Steroid Hormone Receptor Status , 2002, Pathobiology.

[260]  T. Halazonetis,et al.  Genomic instability — an evolving hallmark of cancer , 2010, Nature Reviews Molecular Cell Biology.

[261]  D. Dias-Santagata,et al.  The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. , 2008, Molecular cell.

[262]  Masahiro Watanabe,et al.  Insulin Receptor Substrate-1/SHP-2 Interaction, a Phenotype-dependent Switching Machinery of Insulin-like Growth Factor-I Signaling in Vascular Smooth Muscle Cells* , 2004, Journal of Biological Chemistry.

[263]  Jing Jiang,et al.  ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling. , 2008, Cellular signalling.

[264]  D. Dean,et al.  Tumor initiation via loss of cell contact inhibition versus Ras mutation: Do all roads lead to EMT? , 2010, Cell cycle.

[265]  M. Simon,et al.  Novel insights into the molecular origins and treatment of lung cancer , 2010, Cell cycle.

[266]  Damien Kee,et al.  Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. , 2010, Cancer cell.

[267]  G. Mor,et al.  Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFĸB pathway , 2011, Cell cycle.

[268]  J. Testa,et al.  AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. , 2001, Cancer research.

[269]  J. Carew,et al.  Mechanisms of mTOR inhibitor resistance in cancer therapy , 2011, Targeted Oncology.

[270]  J. Testa,et al.  Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. , 2004, Carcinogenesis.

[271]  K. Coombes,et al.  Low Expression Of PP2A Regulatory Subunit B55α Is Associated With T308 Phosphorylation Of AKT And Shorter Complete Remission Duration In Acute Myeloid Leukemia Patients , 2011, Leukemia.

[272]  D. Alessi,et al.  mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). , 2008, The Biochemical journal.

[273]  K. Podar,et al.  A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways. , 2010, Cell cycle.

[274]  M. Odero,et al.  PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect , 2011, Leukemia.

[275]  W. Kolch,et al.  Mechanism of Suppression of the Raf/MEK/Extracellular Signal-Regulated Kinase Pathway by the Raf Kinase Inhibitor Protein , 2000, Molecular and Cellular Biology.

[276]  Stephen L. Abrams,et al.  Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway , 2011, Leukemia.

[277]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[278]  P. Crespo,et al.  Mxi2 sustains ERK1/2 phosphorylation in the nucleus by preventing ERK1/2 binding to phosphatases. , 2012, The Biochemical journal.

[279]  F. Sotgia,et al.  Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors , 2010, Cell cycle.

[280]  M. Vitale,et al.  Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation , 2012, Cell cycle.

[281]  B. Martín-Castillo,et al.  Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: Induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a , 2011, Cell cycle.

[282]  E. López-Bonet,et al.  AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor , 2009, Cell cycle.

[283]  J. McCubrey,et al.  PI3K/AKT/mTORC1 and MEK/ERK signaling in T-cell acute lymphoblastic leukemia: new options for targeted therapy. , 2012, Advances in biological regulation.

[284]  M. May,et al.  The NFκB paradox: RelB induces and inhibits gene expression , 2011, Cell cycle.

[285]  D. Morrison,et al.  RAF Inhibitor-Induced KSR1/B-RAF Binding and Its Effects on ERK Cascade Signaling , 2011, Current Biology.

[286]  V. Zinzalla,et al.  Activation of mTORC2 by Association with the Ribosome , 2011, Cell.

[287]  V. A. Flørenes,et al.  Expression of activated Akt and PTEN in malignant melanomas: relationship with clinical outcome. , 2005, American journal of clinical pathology.

[288]  C. Dray,et al.  Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: Role in the physiopathology of the disease , 2010, Cell cycle.

[289]  T. Lisse,et al.  Vitamin D , 2011, Cell cycle.

[290]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[291]  M. Blagosklonny.  Rapamycin and quasi-programmed aging: Four years later , 2010, Cell cycle.

[292]  D. Xirodimas,et al.  Mechanism of hypoxia-induced NFκB , 2011 .

[293]  A. Malliri,et al.  The diverse roles of Rac signaling in tumorigenesis , 2011, Cell cycle.

[294]  G. Robert,et al.  Targeting autophagy to fight hematopoietic malignancies , 2010, Cell cycle.

[295]  Huan Yang,et al.  MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. , 2008, Cancer research.

[296]  S. Pileri,et al.  BRAF mutations in hairy-cell leukemia. , 2011, The New England journal of medicine.

[297]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[298]  M. Raffeld,et al.  PTEN gene alterations in lymphoid neoplasms. , 1998, Blood.

[299]  M. Blagosklonny.  Increasing healthy lifespan by suppressing aging in our lifetime: Preliminary proposal , 2010, Cell cycle.

[300]  Lorenzo Galluzzi,et al.  TP53 and MTOR crosstalk to regulate cellular senescence , 2010, Aging.

[301]  O. Carugo,et al.  A Mek1–Mek2 heterodimer determines the strength and duration of the Erk signal , 2009, Nature Structural &Molecular Biology.

[302]  W. Kolch,et al.  Raf-1-associated Protein Phosphatase 2A as a Positive Regulator of Kinase Activation* , 2000, The Journal of Biological Chemistry.

[303]  B. Sander,et al.  Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia , 2005, Leukemia.

[304]  A. Giaccia,et al.  Harnessing synthetic lethal interactions in anticancer drug discovery , 2011, Nature Reviews Drug Discovery.

[305]  L. Larsson,et al.  Cdk2: a key regulator of the senescence control function of Myc , 2010, Aging.

[306]  R. Hruban,et al.  Disruption of p16 and Activation of Kras in Pancreas Increase Ductal Adenocarcinoma Formation and Metastasis in vivo , 2011, Oncotarget.

[307]  E. Morselli,et al.  Defective autophagy control by the p53 rheostat in cancer , 2010, Cell cycle.

[308]  D. A. Foster.  Reduced mortality and moderate alcohol consumption: The phospholipase D-mTOR connection , 2010, Cell cycle.

[309]  Stephen L. Abrams,et al.  The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. , 2010, Cell cycle.

[310]  M. Shaposhnikov,et al.  Pharmacological inhibition of NF-κB prolongs lifespan of Drosophila melanogaster , 2011, Aging.

[311]  K. Vousden,et al.  p53-mediated induction of Noxa and p53AIP1 requires NFκB , 2010 .

[312]  J. Arthur.  MSK activation and physiological roles. , 2008, Frontiers in bioscience : a journal and virtual library.

[313]  M. Tai,et al.  Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma , 2003, Cancer.

[314]  Y. Jang,et al.  Mitotic DNA damage response: Polo-like Kinase-1 is dephosphorylated through ATM-Chk1 pathway , 2010, Cell cycle.

[315]  J. McCubrey,et al.  Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention , 2003, Leukemia.

[316]  N. Sonenberg,et al.  mTOR, translation initiation and cancer , 2006, Oncogene.

[317]  P. Gallant,et al.  Myc’s secret life without Max , 2009, Cell cycle.

[318]  Marco Pahor,et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice , 2009, Nature.

[319]  Stephen L. Abrams,et al.  Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells , 2011, Oncotarget.

[320]  U. Atasoy,et al.  Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis , 2010, Cell cycle.

[321]  P. Vogt,et al.  Understanding PLZF , 2011, Cell cycle.

[322]  A. Thor,et al.  Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions , 2011, Cell cycle.

[323]  F. Bauzon,et al.  Racing to block tumorigenesis after pRb loss: An innocuous point mutation wins with synthetic lethality , 2010, Cell Cycle.

[324]  M. Monden,et al.  PTEN/MMAC1 Mutation and Frequent Loss of Heterozygosity Identified in Chromosome 10q in a Subset of Hepatocellular Carcinomas , 2000, Japanese journal of cancer research : Gann.

[325]  Li Zhao,et al.  Hot-spot mutations in p110α of phosphatidylinositol 3-kinase (PI3K): Differential interactions with the regulatory subunit p85 and with RAS , 2010, Cell cycle.

[326]  M. Narita.  Quality and quantity control of proteins in senescence , 2010, Aging.

[327]  G. Gurtner,et al.  HIF-1alpha dysfunction in diabetes. , 2010, Cell cycle.

[328]  R. Bernards,et al.  Protein phosphatase 2A regulatory subunits and cancer. , 2009, Biochimica et biophysica acta.

[329]  Chien-Jen Chen,et al.  PTEN/MMAC1 mutations in hepatocellular carcinomas , 1999, Oncogene.

[330]  R. Treisman,et al.  Ternary complex factor SAP-1 is required for Erk-mediated thymocyte positive selection , 2004, Nature Immunology.

[331]  N. Perkins,et al.  Regulation of activity and function of the p52 NF-κB subunit following DNA damage , 2010, Cell cycle.

[332]  M. Montminy,et al.  CREB Is a Regulatory Target for the Protein Kinase Akt/PKB* , 1998, The Journal of Biological Chemistry.

[333]  A. Besson,et al.  Oct1 is required for mTOR-induced G1 cell cycle arrest via the control of p27Kip1 expression , 2010, Cell cycle.

[334]  S. Thorgeirsson,et al.  Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. , 2007, The Journal of clinical investigation.

[335]  K. Inoki,et al.  Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling , 2008, The EMBO journal.

[336]  Z. Darżynkiewicz,et al.  Downregulation of uPAR inhibits migration, invasion, proliferation, FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells , 2011, Cell cycle.

[337]  H. Clevers,et al.  LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. , 2009, Physiological reviews.

[338]  N. Schork,et al.  Identification of rare cancer driver mutations by network reconstruction. , 2009, Genome research.

[339]  J. Downward,et al.  Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos. , 1995, Oncogene.

[340]  E. Goncharova,et al.  PI3K/mTORC1 activation in hamartoma syndromes: Therapeutic prospects , 2009, Cell cycle.

[341]  L. Langeberg,et al.  Plugging PKA into ERK scaffolds , 2011, Cell cycle.

[342]  J. Bartek,et al.  Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16ink4a , 2011, Cell cycle.

[343]  M. Mori,et al.  Reduced Expression of PTEN Protein and Its Prognostic Implications in Invasive Ductal Carcinoma of the Breast , 2005, Oncology.

[344]  J. Reis-Filho,et al.  Oncogenic Braf induces melanocyte senescence and melanoma in mice. , 2009, Cancer cell.

[345]  L. Chin,et al.  Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer , 2012, Nature.

[346]  Agnieszka Bronisz,et al.  microRNA-451: A conditional switch controlling glioma cell proliferation and migration , 2010, Cell cycle.

[347]  William R. Sellers,et al.  Advances in the preclinical testing of cancer therapeutic hypotheses , 2011, Nature Reviews Drug Discovery.

[348]  M. Birtwistle,et al.  Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma , 2012, PloS one.

[349]  R. Pierce,et al.  Phenotypic enhancement of thymidylate synthetase pathway inhibitors following ablation of Neil1 DNA glycosylase/lyase , 2010, Cell cycle.

[350]  A. Catling,et al.  Rac-PAK Signaling Stimulates Extracellular Signal-Regulated Kinase (ERK) Activation by Regulating Formation of MEK1-ERK Complexes , 2002, Molecular and Cellular Biology.

[351]  Angel G. Martín.  NFκB anti-apoptotic or pro-apoptotic, maybe both , 2010, Cell Cycle.

[352]  Tae-Wook Chung,et al.  Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells. , 2003, Cancer research.

[353]  B. Stiles.  Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. , 2009, The international journal of biochemistry & cell biology.

[354]  S. Do,et al.  The Hepatitis B Virus-X Protein Activates a Phosphatidylinositol 3-Kinase-dependent Survival Signaling Cascade* , 2001, The Journal of Biological Chemistry.

[355]  S. Campaner,et al.  Myc, Cdk2 and cellular senescence: Old players, new game , 2010, Cell cycle.

[356]  Wh Sit,et al.  Cancer Genomics & Proteomics , 2007 .

[357]  Christopher J. Staples,et al.  Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter , 2008, The Biochemical journal.

[358]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[359]  B. Martín-Castillo,et al.  Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena , 2010, Cell cycle.

[360]  Satoki Nakamura,et al.  Depletion of Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatases 1 and 2 by Bcr-Abl Promotes Chronic Myelogenous Leukemia Cell Proliferation through Continuous Phosphorylation of Akt Isoforms* , 2009, The Journal of Biological Chemistry.

[361]  Massimo Libra,et al.  PIK3CA mutations in human solid tumors: Role in sensitivity to various therapeutic approaches , 2009, Cell cycle.

[362]  R. Hresko,et al.  mTOR·RICTOR Is the Ser473 Kinase for Akt/Protein Kinase B in 3T3-L1 Adipocytes* , 2005, Journal of Biological Chemistry.

[363]  P. Crespo,et al.  p38α Isoform Mxi2 Binds to Extracellular Signal-Regulated Kinase 1 and 2 Mitogen-Activated Protein Kinase and Regulates Its Nuclear Activity by Sustaining Its Phosphorylation Levels , 2003, Molecular and Cellular Biology.

[364]  B. Cochran,et al.  p50cdc37 Acting in Concert with Hsp90 Is Required for Raf-1 Function , 1999, Molecular and Cellular Biology.

[365]  Stephen L. Abrams,et al.  Emerging MEK inhibitors , 2010, Expert opinion on emerging drugs.

[366]  B. Viollet,et al.  Antagonistic control of muscle cell size by AMPK and mTORC1 , 2011, Cell cycle.

[367]  I. Nagtegaal,et al.  BRAF mutation in metastatic colorectal cancer. , 2009, The New England journal of medicine.

[368]  Stephen L. Abrams,et al.  Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health , 2011, Oncotarget.

[369]  J. Christensen,et al.  Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab , 2011, Cell cycle.

[370]  A. Weiss,et al.  Induction of NF-kappaB by the Akt/PKB kinase. , 1999, Current biology : CB.

[371]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[372]  S H Lee,et al.  BRAF mutations in non-Hodgkin's lymphoma , 2003, British Journal of Cancer.

[373]  T. Hunter,et al.  Inappropriate Activation of the TSC/Rheb/mTOR/S6K Cassette Induces IRS1/2 Depletion, Insulin Resistance, and Cell Survival Deficiencies , 2004, Current Biology.

[374]  L. Peso,et al.  Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. , 1997, Science.

[375]  C. Maki.  Decision-making by p53 and mTOR , 2010, Aging.

[376]  Jacquelyne S Poon,et al.  Both lipid- and protein-phosphatase activities of PTEN contribute to the p53-PTEN anti-invasion pathway , 2010, Cell cycle.

[377]  A. Pinchera,et al.  BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. , 2004, The Journal of clinical endocrinology and metabolism.

[378]  M. Ladanyi,et al.  Coexistence of PIK3CA and Other Oncogene Mutations in Lung Adenocarcinoma–Rationale for Comprehensive Mutation Profiling , 2011, Molecular Cancer Therapeutics.

[379]  J. Auwerx,et al.  Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. , 2008, Cell metabolism.

[380]  Helen Pickersgill,et al.  Oncogenic BRAF Regulates Melanoma Proliferation through the Lineage Specific Factor MITF , 2008, PloS one.

[381]  R. Memmott,et al.  Akt-dependent and -independent mechanisms of mTOR regulation in cancer. , 2009, Cellular signalling.

[382]  Dario R Alessi,et al.  Metformin and reduced risk of cancer in diabetic patients , 2005, BMJ : British Medical Journal.

[383]  J. Tamburini,et al.  LKB1/AMPK/mTOR signaling pathway in hematological malignancies: From metabolism to cancer cell biology , 2011, Cell cycle.

[384]  R. Maestro,et al.  Overexpression of TWIST2 correlates with poor prognosis in Head and Neck Squamous Cell Carcinomas , 2011, OncoTarget.

[385]  M. Sahin.  Eph receptor and mTOR pathway crosstalk: Implications for cancer , 2010, Cell cycle.

[386]  T. Pandita,et al.  Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair , 2009, Cell cycle.

[387]  D. Guertin,et al.  Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton , 2004, Current Biology.

[388]  H. Schaeffer,et al.  MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. , 1998, Science.

[389]  M. Lisanti,et al.  Reviewing once more the c-myc and Ras collaboration , 2011, Cell cycle.

[390]  A. Joe,et al.  Oncogene addiction. , 2008, Cancer research.

[391]  N. Jordan,et al.  Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer , 2011, Cell cycle.

[392]  E. Shtivelman,et al.  CC3/TIP30 regulates metabolic adaptation of tumor cells to glucose limitation , 2010, Cell cycle.