TY - JOUR
T1 - Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence
AU - Scaglioni, Pier Paolo
AU - Rabellino, Andrea
AU - Yung, Thomas M.
AU - Bernardi, Rosa
AU - Choi, Sooyeon
AU - Konstantinidou, Georgia
AU - Nardella, Caterina
AU - Cheng, Ke
AU - Pandolfi, Pier Paolo
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
KW - MTOR
KW - Oncogene-induced cellular senescence
KW - Oncogenic K-RAS
KW - PML
KW - Protein translation
UR - http://www.scopus.com/inward/record.url?scp=84863456310&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863456310&partnerID=8YFLogxK
U2 - 10.1002/emmm.201200233
DO - 10.1002/emmm.201200233
M3 - Article
C2 - 22359342
AN - SCOPUS:84863456310
SN - 1757-4676
VL - 4
SP - 594
EP - 602
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
ER -