Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence

Pier Paolo Scaglioni, Andrea Rabellino, Thomas M. Yung, Rosa Bernardi, Sooyeon Choi, Georgia Konstantinidou, Caterina Nardella, Ke Cheng, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)594-602
Number of pages9
JournalEMBO Molecular Medicine
Volume4
Issue number7
DOIs
StatePublished - Jul 1 2012

Keywords

  • MTOR
  • Oncogene-induced cellular senescence
  • Oncogenic K-RAS
  • PML
  • Protein translation

ASJC Scopus subject areas

  • Molecular Medicine

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    Scaglioni, P. P., Rabellino, A., Yung, T. M., Bernardi, R., Choi, S., Konstantinidou, G., Nardella, C., Cheng, K., & Pandolfi, P. P. (2012). Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Molecular Medicine, 4(7), 594-602. https://doi.org/10.1002/emmm.201200233