Open AccessTranslation‐dependent mechanisms lead to PML upregulation and mediate oncogenic K‐RAS‐induced cellular senescence
Author(s) -
Scaglioni Pier Paolo,
Rabellino Andrea,
Yung Thomas M.,
Bernardi Rosa,
Choi Sooyeon,
Konstantinidou Georgia,
Nardella Caterina,
Cheng Ke,
Pandolfi Pier Paolo
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200233
Subject(s) - downregulation and upregulation , biology , microbiology and biotechnology , promyelocytic leukemia protein , cancer research , eif4e , translation (biology) , pi3k/akt/mtor pathway , mediator , polysome , untranslated region , messenger rna , signal transduction , nuclear protein , transcription factor , genetics , rna , gene , ribosome
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.