HdmX overexpression inhibits oncogene induced cellular senescence

Cellular senescence is an irreversible state of terminal growth arrest that requires functional p53.  Acting to block tumor formation, induction of senescence has also been demonstrated to contribute to tumor clearance via the immune system following p53 reactivation. 1, 2 The Hdm2-antagonist, Nutli...

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Published in:Cell cycle (Georgetown, Tex.) Tex.), 2010-08, Vol.9 (16), p.3396-3402
Main Authors: Miller, Kelly R., Kelley, Kevin, Tuttle, Rebecca, Berberich, Steven
Format: Article
Language:English
Subjects:
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Line
Cellular Senescence
Cycle
Fibroblasts - metabolism
Humans
Landes
Mutation
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Organogenesis
Proteins
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-mdm2 - metabolism
Proto-Oncogene Proteins p21(ras) - metabolism
RNA Interference
Tumor Suppressor Protein p53 - metabolism
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Summary:Cellular senescence is an irreversible state of terminal growth arrest that requires functional p53.  Acting to block tumor formation, induction of senescence has also been demonstrated to contribute to tumor clearance via the immune system following p53 reactivation. 1, 2 The Hdm2-antagonist, Nutlin-3a, has been shown to reactivate p53 and induce a quiescent state in various cancer cell lines, 3, 4 similar to the G1 arrest observed upon RNAi targeting of Hdm2 in MCF7 breast cancer. 5 In the present study we show that HdmX, a negative regulator of p53, impacts the senescence pathway.  Specifically, overexpression of HdmX blocks Ras mediated senescence in primary human fibroblasts.  The interaction of HdmX with p53 and the re-localization of HdmX to the nucleus through Hdm2 association appear to be required for this activity.  Furthermore, inhibiting HdmX in prostate adenocarcinoma cells expressing wild-type p53, mutant Ras and high levels of HdmX induced cellular senescence as measured by an increase in irreversible b-galactosidase staining.  Together these results suggest that HdmX overexpression may contribute to tumor formation by blocking senescence and that targeting HdmX may represent an attractive anti-cancer therapeutic approach.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.9.16.12779