Document Detail


Racing to block tumorigenesis after pRb loss: an innocuous point mutation wins with synthetic lethality.
MedLine Citation:
PMID:  20505340     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A major goal of tumor suppressor research is to neutralize the tumorigenic effects of their loss. Since loss of pRb does not induce tumorigenesis in many types of cells, natural mechanisms may neutralize the tumorigenic effects of pRb loss in these cells. For susceptible cells, neutralizing the tumorigenic effects of pRb loss could logically be achieved by correcting the deregulated activities of pRb targets to render pRb-deficient cells less abnormal. This line of research has unexpectedly revealed that knocking out the pRb target Skp2 did not render Rb1 deficient cells less abnormal but, rather, induced apoptosis in them, thereby completely blocking tumorigenesis in Rb1+/- mice and after targeted deletion of Rb1 in pituitary intermediate lobe (IL). Skp2 is a substrate-recruiting component of the SCFSkp2 E3 biquitin ligase; one of its substrates is Thr187-phosphorylated p27Kip1. A p27T187A knockin (KI) mutation phenocopied Skp2 knockout (KO) in inducing apoptosis following Rb1 loss. Thus, Skp2 KO or p27T187A KI are synthetic lethal with pRb inactivation. Since homozygous p27T187A KI mutations show no adverse effects in mice, inhibiting p27T187 phosphorylation or p27T187p ubiquitination could be a highly therapeutic and minimally toxic intervention strategy for pRb deficiency-induced tumorigenesis.
Authors:
Frederick Bauzon; Liang Zhu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2010-06-01
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2011-05-17     Completed Date:  2011-09-09     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2118-23     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
E2F Transcription Factors / metabolism
Genes, Lethal
Mice
Mutation*
Neoplasms / genetics*,  pathology
Point Mutation
Retinoblastoma Protein / antagonists & inhibitors,  genetics*,  metabolism
S-Phase Kinase-Associated Proteins / metabolism
Tumor Suppressor Protein p53 / metabolism
Ubiquitination
Grant Support
ID/Acronym/Agency:
R01 CA131421/CA/NCI NIH HHS; R01 CA131421-01A2/CA/NCI NIH HHS; R01CA131421/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/E2F Transcription Factors; 0/Retinoblastoma Protein; 0/S-Phase Kinase-Associated Proteins; 0/Tumor Suppressor Protein p53; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27
Comments/Corrections

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