Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence Journal Article
| Authors: | Scaglioni, P. P.; Rabellino, A.; Yung, T. M.; Bernardi, R.; Choi, S.; Konstantinidou, G.; Nardella, C.; Cheng, K.; Pandolfi, P. P. |
| Article 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. © 2012 EMBO Molecular Medicine. |
| Keywords: | signal transduction; dna-binding proteins; raf protein; animals; mice; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; cell line; in vivo study; in vitro study; protein p53; mice, transgenic; transcription factors; nuclear proteins; leukemia, promyelocytic, acute; messenger rna; protein synthesis; 5' untranslated region; mammalian target of rapamycin; enzyme inactivation; tumor suppressor proteins; promyelocytic leukemia; fibroblasts; initiation factor 4e; tumor suppressor protein p53; polysome; ras protein; upregulation; ras proteins; up-regulation; k ras protein; cell aging; mtor; 5' untranslated regions; promyelocytic leukemia protein; mitogen-activated protein kinase 1; mitogen-activated protein kinase 3; pml; tor serine-threonine kinases; oncogene-induced cellular senescence; oncogenic k-ras; protein translation |
| Journal Title: | EMBO Molecular Medicine |
| Volume: | 4 |
| Issue: | 7 |
| ISSN: | 1757-4676 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2012-07-01 |
| Start Page: | 594 |
| End Page: | 602 |
| Language: | English |
| DOI: | 10.1002/emmm.201200233 |
| PROVIDER: | scopus |
| PUBMED: | 22359342 |
| PMCID: | PMC3407947 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2012" - "Source: Scopus" |
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