Multiple Roles of the PI3K/PKB (Akt) Pathway in Cell Cycle Progression

As its role in tumor progression emerges, the PI3K/PKB (Akt) pathway presents an appealing cancer therapeutic target. Recent studies have investigated the mechanisms underlying the tumor-promoting effects of this pathway. PKB triggers a network that positively regulates G1/S cell cycle progression through inactivation of GSK3-beta, leading to increased cyclin D1, and inhibition of Forkhead family transcription factors and the tumor suppressor tuberin (TSC2), leading to reduction of p27Kip1. The identification of p21Waf1/Cip1 and p27Kip1 as novel substrates of PKB provided new insights into mechanisms whereby hyperactivation of this lipid signaling pathway may lead to cell cycle deregulation in human cancers. The PI3K pathway may also play a key role in the G2/M transition and its constitutive activation may lead to defects in DNA damage checkpoint control.

[1]  Stefanie Dimmeler,et al.  Akt-Dependent Phosphorylation of p21Cip1 Regulates PCNA Binding and Proliferation of Endothelial Cells , 2001, Molecular and Cellular Biology.

[2]  P. Beer-Romero,et al.  Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. , 1995, Science.

[3]  J Wade Harper,et al.  Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

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

[5]  R. Medema,et al.  AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1 , 2000, Nature.

[6]  Joseph R. Nevins,et al.  Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F , 1997, Nature.

[7]  D R Alessi,et al.  PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? , 2001, Journal of cell science.

[8]  G. Cattoretti,et al.  Localization and expression of p27KIP1 in multistage colorectal carcinogenesis. , 1998, Cancer research.

[9]  S. R. Datta,et al.  DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein , 2002, Science.

[10]  Y Taya,et al.  Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. , 2000, Genes & development.

[11]  L. Hengst,et al.  CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. , 2003, Molecular biology of the cell.

[12]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Ramaswamy,et al.  Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. , 2002, The Journal of clinical investigation.

[14]  K. Ball,et al.  Reversible Phosphorylation at the C-terminal Regulatory Domain of p21Waf1/Cip1 Modulates Proliferating Cell Nuclear Antigen Binding* , 2000, The Journal of Biological Chemistry.

[15]  J. Woodgett,et al.  Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. , 1998, The Biochemical journal.

[16]  A. Gartel,et al.  Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. , 2003, Experimental cell research.

[17]  M. Pagano,et al.  Enhanced Ribosomal Association of p27Kip1 mRNA Is a Mechanism Contributing to Accumulation during Growth Arrest* , 1997, The Journal of Biological Chemistry.

[18]  N. Takuwa,et al.  Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts , 1997, Molecular and cellular biology.

[19]  J L Cleveland,et al.  Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. , 2000, Genes & development.

[20]  M. Hung,et al.  Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells , 2001, Nature Cell Biology.

[21]  P. Tsichlis,et al.  Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  H. Yoshida,et al.  Akt inhibits Myt1 in the signalling pathway that leads to meiotic G2/M-phase transition , 2002, Nature Cell Biology.

[23]  D. Tindall,et al.  Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. , 2001, Endocrinology.

[24]  T. T. Schwindt,et al.  ACTH promotion of p27(Kip1) induction in mouse Y1 adrenocortical tumor cells is dependent on both PKA activation and Akt/PKB inactivation. , 2002, Biochemistry.

[25]  C. Marshall,et al.  Activated MEK Stimulates Expression of AP-1 Components Independently of Phosphatidylinositol 3-Kinase (PI3-Kinase) but Requires a PI3-Kinase Signal To Stimulate DNA Synthesis , 1999, Molecular and Cellular Biology.

[26]  Hong Sun,et al.  PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Martínez-A,et al.  Forkhead transcription factors contribute to execution of the mitotic programme in mammals , 2001, Nature.

[28]  Motoo Nagane,et al.  Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. , 2002, Cancer research.

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

[30]  C. Arteaga,et al.  Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. , 2002, Cancer research.

[31]  N. Walworth.  DNA damage: Chk1 and Cdc25, more than meets the eye. , 2001, Current opinion in genetics & development.

[32]  Rosalie C Sears,et al.  Signaling Networks That Link Cell Proliferation and Cell Fate* , 2002, The Journal of Biological Chemistry.

[33]  Carlos L. Arteaga,et al.  PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization , 2002, Nature Medicine.

[34]  James M. Roberts,et al.  A new pathway for mitogen-dependent Cdk2 regulation uncovered in p27Kip1-deficient cells , 1999, Current Biology.

[35]  I. Macara,et al.  Inhibition of Nuclear Import by Protein Kinase B (Akt) Regulates the Subcellular Distribution and Activity of the Forkhead Transcription Factor AFX , 2001, Molecular and Cellular Biology.

[36]  Andrea C. Carrano,et al.  Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. , 1999, Genes & development.

[37]  W. Krek,et al.  The F‐box protein Skp2 is a ubiquitylation target of a Cul1‐based core ubiquitin ligase complex: evidence for a role of Cul1 in the suppression of Skp2 expression in quiescent fibroblasts , 2000, The EMBO journal.

[38]  D. Roymans,et al.  Phosphatidylinositol 3-kinases in tumor progression. , 2001, European journal of biochemistry.

[39]  R. Yeung,et al.  Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Andreas Sewing,et al.  Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27Kip1 binding to newly formed complexes , 1997, Oncogene.

[41]  A. Sytkowski,et al.  Erythropoietin Activates Two Distinct Signaling Pathways Required for the Initiation and the Elongation of c-myc * , 2001, The Journal of Biological Chemistry.

[42]  T. Tamiya,et al.  Expression of cell cycle regulator p27Kip1 is correlated with survival of patients with astrocytoma. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  E. Lam,et al.  Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D , 2002, Molecular and Cellular Biology.

[44]  E. Lam,et al.  Inhibition of the Phosphoinositide 3-Kinase Pathway Induces a Senescence-like Arrest Mediated by p27Kip1 * , 2000, The Journal of Biological Chemistry.

[45]  M. Koegl,et al.  The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some, but not all, growth factors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Andrius Kazlauskas,et al.  Growth-factor-dependent mitogenesis requires two distinct phases of signalling , 2001, Nature Cell Biology.

[47]  T. Goldsworthy,et al.  Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines. , 1995, The American journal of pathology.

[48]  H. Iwasaki,et al.  Critical role for Gab2 in transformation by BCR/ABL. , 2002, Cancer cell.

[49]  G. MacGrogan,et al.  LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast. , 1998, Human pathology.

[50]  K. Nakayama,et al.  Degradation of p27 Kip1 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination Pathway* , 2001, The Journal of Biological Chemistry.

[51]  M. Emmert-Buck,et al.  Loss of heterozygosity is detected at chromosomes 1p35-36 (NB), 3p25 (VHL), 16p13 (TSC2/PKD1), and 17p13 (TP53) in microdissected apocrine carcinomas of the breast. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[52]  J. Pouysségur,et al.  Cyclin D1 Expression Is Regulated Positively by the p42/p44MAPK and Negatively by the p38/HOGMAPK Pathway* , 1996, The Journal of Biological Chemistry.

[53]  S. Elledge,et al.  Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. , 1997, Science.

[54]  H. Onda,et al.  Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells , 2002, Oncogene.

[55]  J. Baldassare,et al.  Ras-stimulated Extracellular Signal-related Kinase 1 and RhoA Activities Coordinate Platelet-derived Growth Factor-induced G1 Progression through the Independent Regulation of Cyclin D1 and p27KIP1 * , 1997, The Journal of Biological Chemistry.

[56]  Steven J. Marygold,et al.  Growth Signaling: TSC Takes Its Place , 2002, Current Biology.

[57]  Mikhail V. Blagosklonny,et al.  The Restriction Point of the Cell Cycle , 2002, Cell cycle.

[58]  C. Eng,et al.  PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. , 2001, Human molecular genetics.

[59]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

[60]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[61]  P. Libby,et al.  PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells , 1989, Cell.

[62]  Alfonso Bellacosa,et al.  Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer , 2002, Nature Medicine.

[63]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[64]  Andrius Kazlauskas,et al.  PDGF induces an early and a late wave of PI 3-kinase activity, and only the late wave is required for progression through G1 , 1999, Current Biology.

[65]  D. Stokoe,et al.  A Role for PI 3-Kinase and PKB Activity in the G2/M Phase of the Cell Cycle , 2002, Current Biology.

[66]  W. Ansorge,et al.  Induction of cyclin E–cdk2 kinase activity, E2F‐dependent transcription and cell growth by Myc are genetically separable events , 2000, The EMBO journal.

[67]  J. Massagué,et al.  Breast cancer banishes p27 from nucleus , 2002, Nature Medicine.

[68]  J. Slingerland,et al.  Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor beta-mediated G(1) arrest. , 2002, Molecular and cellular biology.

[69]  Bruno Amati,et al.  Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1 , 1997, The EMBO journal.

[70]  Austin G Smith,et al.  Signalling, cell cycle and pluripotency in embryonic stem cells. , 2002, Trends in cell biology.

[71]  James M. Roberts,et al.  Cyclin E-CDK2 is a regulator of p27Kip1. , 1997, Genes & development.

[72]  L. Field,et al.  Enhanced cardiomyocyte DNA synthesis during myocardial hypertrophy in mice expressing a modified TSC2 transgene. , 2000, Circulation research.

[73]  M. Loda,et al.  Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma. , 1998, Cancer research.

[74]  R. Mamillapalli,et al.  PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27KIP1 through the ubiquitin E3 ligase SCFSKP2 , 2001, Current Biology.

[75]  M. Pagano,et al.  Regulation of the Cdk inhibitor p27 and its deregulation in cancer , 2000, Journal of cellular physiology.

[76]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[77]  J. Roberts,et al.  Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes , 1994, Molecular and cellular biology.

[78]  James M. Roberts,et al.  lnterleukin-2-mediated elimination of the p27Kipl cyclin-dependent kinase inhibitor prevented by rapamycin , 1994, Nature.

[79]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[80]  J. Raleigh,et al.  The G(2) DNA damage checkpoint targets both Wee1 and Cdc25. , 2000, Journal of cell science.

[81]  S. Cook,et al.  Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells , 1999, Oncogene.

[82]  P. Pandolfi,et al.  Activation of Akt/Protein Kinase B Overcomes a G2/M Cell Cycle Checkpoint Induced by DNA Damage , 2002, Molecular and Cellular Biology.

[83]  J. Downward,et al.  Multiple Ras Effector Pathways Contribute to G1Cell Cycle Progression* , 1999, The Journal of Biological Chemistry.

[84]  M. Loda,et al.  BCR/ABL Regulates Expression of the Cyclin-dependent Kinase Inhibitor p27Kip1 through the Phosphatidylinositol 3-Kinase/AKT Pathway* , 2000, The Journal of Biological Chemistry.

[85]  C. Lacombe,et al.  Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma , 2002, Oncogene.

[86]  Pier Paolo Pandolfi,et al.  The Multiple Roles of PTEN in Tumor Suppression , 2000, Cell.

[87]  James M. Roberts,et al.  A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase , 2001, Nature.

[88]  C. Sherr.  The Pezcoller lecture: cancer cell cycles revisited. , 2000, Cancer research.

[89]  D. Alessi,et al.  TSC1–TSC2: a complex tale of PKB-mediated S6K regulation , 2002, Nature Cell Biology.

[90]  Ying Li,et al.  AKT/PKB Phosphorylation of p21Cip/WAF1 Enhances Protein Stability of p21Cip/WAF1 and Promotes Cell Survival* , 2002, The Journal of Biological Chemistry.

[91]  P. Russell,et al.  Cell cycle regulation of human WEE1. , 1995, The EMBO journal.

[92]  M. Piris,et al.  Anomalous high p27/KIP1 expression in a subset of aggressive B-cell lymphomas is associated with cyclin D3 overexpression. p27/KIP1-cyclin D3 colocalization in tumor cells. , 1999, Blood.

[93]  P. Nurse,et al.  Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation , 1997, The EMBO journal.

[94]  L. Hengst,et al.  Translational Control of p27Kip1 Accumulation During the Cell Cycle , 1996, Science.

[95]  D. Linnekin,et al.  Early signaling pathways activated by c-Kit in hematopoietic cells. , 1999, The international journal of biochemistry & cell biology.

[96]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[97]  B. Amati,et al.  Growth arrest by the cyclin‐dependent kinase inhibitor p27Kip1 is abrogated by c‐Myc. , 1996, The EMBO journal.

[98]  J. Slingerland,et al.  PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest , 2002, Nature Medicine.

[99]  X. Wang,et al.  Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45 , 1999, Oncogene.

[100]  J. Mestan,et al.  Skp2 is oncogenic and overexpressed in human cancers , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[101]  Takashi Tsuruo,et al.  Akt-dependent Phosphorylation of p27Kip1Promotes Binding to 14-3-3 and Cytoplasmic Localization* , 2002, The Journal of Biological Chemistry.

[102]  M. Mori,et al.  Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. , 2002, Cancer research.

[103]  R. Weinberg,et al.  Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. , 1994, Genes & development.

[104]  E. Lam,et al.  Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors , 2002, Molecular and Cellular Biology.