Translation-Dependent Mechanisms Lead to PML Upregulation and Mediate Oncogenic K-RAS-Induced Cellular Senescence
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Author
Scaglioni, Pier Paolo
Rabellino, Andrea
Yung, Thomas M.
Bernardi, Rosa
Choi, Sooyeon
Konstantinidou, Georgia
Nardella, Caterina
Cheng, Ke
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https://doi.org/10.1002/emmm.201200233Metadata
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Scaglioni, Pier Paolo, Andrea Rabellino, Thomas M. Yung, Rosa Bernardi, Sooyeon Choi, Georgia Konstantinidou, Caterina Nardella, Ke Cheng, and Pier Paolo Pandolfi. 2012. Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Molecular Medicine 4(7): 594-602.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 \(PML-RAR\alpha\) 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407947Terms of Use
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