title: Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence.
abstract: Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the PML-RARα oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5' untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL.
authors.affiliation: Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. pier.scaglioni@utsouthwestern.edu
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
authors.forename: Andrea
authors.initials: A
authors.lastname: Rabellino
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Yung
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Choi
authors.forename: Georgia
authors.initials: G
authors.lastname: Konstantinidou
authors.forename: Caterina
authors.initials: C
authors.lastname: Nardella
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins