title: P19 H-ras induces G1/S phase delay maintaining cells in a reversible quiescence state.
abstract: BACKGROUND
  Three functional c-ras genes, known as c-H-ras, c-K-ras, and c-N-ras, have been largely studied in mammalian cells with important insights into normal and tumorigenic cellular signal transduction events. Two K-Ras mRNAs are obtained from the same pre-mRNA by alternative splicing. H-Ras pre-mRNA can also be alternatively spliced in the IDX and 4A terminal exons, yielding the p19 and p21 proteins, respectively. However, despite the Ras gene family's established role in tumorigenic cellular signal transduction events, little is known about p19 function. Previous results showed that p19 did not interact with two known p21 effectors, Raf1 and Rin1, but was shown to interact with RACK1, a scaffolding protein that promotes multi-protein complexes in different signaling pathways (Cancer Res 2003, 63 p5178). This observation suggests that p19 and p21 play differential and complementary roles in the cell.
  
  
  RESULTS
  We found that p19 regulates telomerase activity through its interaction with p73alpha/beta proteins. We also found that p19 overexpression induces G1/S phase delay; an observation that correlates with hypophosphorylation of both Akt and p70SK6. Similarly, we also observed that FOXO1 is upregulated when p19 is overexpressed. The three observations of (1) hypophosphorylation of Akt, (2) G1/S phase delay and (3) upregulation of FOXO1 lead us to conclude that p19 induces G1/S phase delay, thereby maintaining cells in a reversible quiescence state and preventing entry into apoptosis. We then assessed the effect of p19 RNAi on HeLa cell growth and found that p19 RNAi increases cell growth, thereby having the opposite effect of arrest of the G1/S phase or producing a cellular quiescence state.
  
  
  CONCLUSIONS
  Interestingly, p19 induces FOXO1 that in combination with the G1/S phase delay and hypophosphorylation of both Akt and p70SK6 leads to maintenance of a reversible cellular quiescence state, thereby preventing entry into apoptosis.
authors.affiliation: Unidad de Splicing, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Camats
authors.forename: Mariette
authors.initials: M
authors.lastname: Kokolo
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Heesom
authors.forename: Michael
authors.initials: M
authors.lastname: Ladomery
authors.forename: Montse
authors.initials: M
authors.lastname: Bach-Elias
mesh_terms: D001483:Base Sequence; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D040901:Proteomics; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D034622:RNA Interference; D016196:S Phase; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D019098:Telomerase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)