Signaling to the ribosome in cancer—It is more than just mTORC1

It is becoming increasingly clear that dysregulation of protein synthesis contributes to a range of diseases characterized by tissue overgrowth. These include arterial stenosis, cardiac hypertrophy, hamartomas, and cancer. The central hub for the regulation of protein synthesis is the ribosome, where the key signaling pathways downstream of RAS, MYC, and phosphatidylinositol‐3‐kinase (PI3K) converge to confer exquisite, coordinated control of ribosome synthesis and function. Such cooperation ensures strict regulation of protein synthesis rates and cell growth. This review will focus on the role the PI3K/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway plays in regulating ribosome function during both health and disease, its interaction with the other key growth regulatory pathways activated by RAS and MYC, and the therapeutic potential for targeting this network. © 2011 IUBMB IUBMB Life, 63(2): 79–85, 2011

[1]  I. Grummt,et al.  The RNA polymerase i transcription machinery , 2011 .

[2]  R. Hannan,et al.  Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. , 2011, Cancer research.

[3]  T. Hunter,et al.  Protein kinase signaling networks in cancer. , 2011, Current opinion in genetics & development.

[4]  G. McArthur,et al.  c-MYC coordinately regulates ribosomal gene chromatin remodeling and Pol I availability during granulocyte differentiation , 2010, Nucleic acids research.

[5]  V. Heinemann,et al.  Ras mutational status is a biomarker for resistance to EGFR inhibitors in colorectal carcinoma. , 2010, Anticancer research.

[6]  E. Raymond,et al.  New inhibitors of the mammalian target of rapamycin signaling pathway for cancer , 2010, Expert opinion on investigational drugs.

[7]  B. Ramsbottom,et al.  mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1 , 2010, Proceedings of the National Academy of Sciences.

[8]  Andrew D. Sharrocks,et al.  Coordinated control of the gene expression machinery. , 2010, Trends in genetics : TIG.

[9]  B. Ebert,et al.  Ribosomopathies: human disorders of ribosome dysfunction. , 2010, Blood.

[10]  Hee-Jin Kim,et al.  A novel initiation codon mutation in the ribosomal protein S17 gene (RPS17) in a patient with Diamond‐Blackfan anemia , 2010, Pediatric blood & cancer.

[11]  E. Choi,et al.  Pathological roles of MAPK signaling pathways in human diseases. , 2010, Biochimica et biophysica acta.

[12]  D. Felsher,et al.  MYC as a regulator of ribosome biogenesis and protein synthesis , 2010, Nature Reviews Cancer.

[13]  P. Richardson,et al.  Clinical and Translational Studies of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed or Relapsed/Refractory Waldenström's Macroglobulinemia , 2010, Clinical Cancer Research.

[14]  I. Grummt,et al.  The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer. , 2010, Annual review of pharmacology and toxicology.

[15]  B. Hemmings,et al.  Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. , 2010, Current topics in microbiology and immunology.

[16]  D. Ruggero The role of Myc-induced protein synthesis in cancer. , 2009, Cancer research.

[17]  M. Adamo,et al.  Current Perspectives on Akt Akt-ivation and Akt-ions , 2009, Experimental biology and medicine.

[18]  D. Sabatini,et al.  mTOR signaling at a glance , 2009, Journal of Cell Science.

[19]  A. Bardelli,et al.  Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer , 2009, Journal of the National Cancer Institute.

[20]  Amy Lin,et al.  Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. , 2009, Cancer research.

[21]  R. Hannan,et al.  The role of UBF in regulating the structure and dynamics of transcriptionally active rDNA chromatin , 2009, Epigenetics.

[22]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

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

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

[25]  J. Blenis,et al.  Molecular mechanisms of mTOR-mediated translational control , 2009, Nature Reviews Molecular Cell Biology.

[26]  J. Blenis,et al.  Not all substrates are treated equally: Implications for mTOR, rapamycin-resistance, and cancer therapy , 2009, Cell cycle.

[27]  B. Jiang,et al.  PI3K/PTEN signaling in angiogenesis and tumorigenesis. , 2009, Advances in cancer research.

[28]  F. Luft The rise of a ribosomopathy and increased cancer risk , 2009, Journal of Molecular Medicine.

[29]  Tom Moss,et al.  UBF levels determine the number of active ribosomal RNA genes in mammals , 2008, The Journal of cell biology.

[30]  G. Semenza,et al.  Induction of HIF‐1α expression by intermittent hypoxia: Involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR , 2008, Journal of cellular physiology.

[31]  Robert J White RNA polymerases I and III, non-coding RNAs and cancer. , 2008, Trends in genetics : TIG.

[32]  M. Dai,et al.  Crosstalk between c‐Myc and ribosome in ribosomal biogenesis and cancer , 2008, Journal of cellular biochemistry.

[33]  R. Pearson,et al.  Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. , 2008, Blood.

[34]  T. Moss,et al.  The splice variants of UBF differentially regulate RNA polymerase I transcription elongation in response to ERK phosphorylation , 2008, Nucleic acids research.

[35]  J. Blenis,et al.  SKAR Links Pre-mRNA Splicing to mTOR/S6K1-Mediated Enhanced Translation Efficiency of Spliced mRNAs , 2008, Cell.

[36]  L. Platanias,et al.  Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway* , 2008, Journal of Biological Chemistry.

[37]  T. Golub,et al.  Identification of RPS14 as a 5q- syndrome gene by RNA interference screen , 2007, Nature.

[38]  A. Nakashima,et al.  The Proline-rich Akt Substrate of 40 kDa (PRAS40) Is a Physiological Substrate of Mammalian Target of Rapamycin Complex 1* , 2007, Journal of Biological Chemistry.

[39]  Timothy J. Griffin,et al.  Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 , 2007, Nature Cell Biology.

[40]  R. Pearson,et al.  Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function , 2007, Growth factors.

[41]  I. Grummt,et al.  Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases , 2006, Oncogene.

[42]  C. Proud,et al.  The mTOR pathway in the control of protein synthesis. , 2006, Physiology.

[43]  Brian Raught,et al.  The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity , 2006, The EMBO journal.

[44]  O. Meyuhas,et al.  Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. , 2006, Trends in biochemical sciences.

[45]  K. Al-Kuraya,et al.  Role of phosphatidylinositol 3'-kinase/AKT pathway in diffuse large B-cell lymphoma survival. , 2005, Blood.

[46]  T. Moss,et al.  A housekeeper with power of attorney: the rRNA genes in ribosome biogenesis , 2006, Cellular and Molecular Life Sciences.

[47]  J. Testa,et al.  Perturbations of the AKT signaling pathway in human cancer , 2005, Oncogene.

[48]  I. Campbell,et al.  PIK3CA Mutations in Ovarian Cancer , 2005, Clinical Cancer Research.

[49]  Carla Grandori,et al.  c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I , 2005, Nature Cell Biology.

[50]  Wayne A. Phillips,et al.  Mutation of the PIK3CA Gene in Ovarian and Breast Cancer , 2004, Cancer Research.

[51]  R. Pearson,et al.  MAD1 and c‐MYC regulate UBF and rDNA transcription during granulocyte differentiation , 2004, The EMBO journal.

[52]  P. Vogt,et al.  An essential role for protein synthesis in oncogenic cellular transformation , 2004, Oncogene.

[53]  S. Lowe,et al.  Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy , 2004, Nature.

[54]  R. Pearson,et al.  mTOR-Dependent Regulation of Ribosomal Gene Transcription Requires S6K1 and Is Mediated by Phosphorylation of the Carboxy-Terminal Activation Domain of the Nucleolar Transcription Factor UBF† , 2003, Molecular and Cellular Biology.

[55]  R. Hannan,et al.  Cardiac hypertrophy: A matter of translation , 2003, Clinical and experimental pharmacology & physiology.

[56]  P. Pandolfi,et al.  Does the ribosome translate cancer? , 2003, Nature Reviews Cancer.

[57]  I. Grummt,et al.  ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is required for RNA polymerase I transcription and cell growth. , 2003, Molecular cell.

[58]  R. Hannan,et al.  Increased expression of UBF is a critical determinant for rRNA synthesis and hypertrophic growth of cardiac myocytes , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[59]  H. Moses,et al.  Salicylate-induced Growth Arrest Is Associated with Inhibition of p70s6k and Down-regulation of c-Myc, Cyclin D1, Cyclin A, and Proliferating Cell Nuclear Antigen* , 2000, The Journal of Biological Chemistry.

[60]  O. Meyuhas Synthesis of the translational apparatus is regulated at the translational level. , 2000, European journal of biochemistry.

[61]  H. Zentgraf,et al.  TIF‐IA, the factor mediating growth‐dependent control of ribosomal RNA synthesis, is the mammalian homolog of yeast Rrn3p , 2000, EMBO reports.

[62]  R H Hruban,et al.  Progression model for pancreatic cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[63]  C. Proud,et al.  Activation of mRNA translation in rat cardiac myocytes by insulin involves multiple rapamycin-sensitive steps. , 2000, American journal of physiology. Heart and circulatory physiology.

[64]  Stefano Fumagalli,et al.  Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase , 1998, The EMBO journal.

[65]  S. Desrivières,et al.  Rapamycin Inhibition of the G1 to S Transition Is Mediated by Effects on Cyclin D1 mRNA and Protein Stability* , 1998, The Journal of Biological Chemistry.

[66]  R. Pearson,et al.  Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k , 1997, The EMBO journal.