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A role for c-Abl in cell senescence and spontaneous immortalization.
MedLine Citation:
PMID:  22791394     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
c-Abl is a proto-oncogene that is essential for mouse development and tissue homeostasis. Misregulation of c-Abl, as seen in the constitutively active BCR-ABL, is the leading cause of human chronic myeloid leukemia. However, how the Abl proteins execute their functions still remains largely unknown. Here, we report an important role for c-Abl in replicative senescence and immortalization by regulating the expression of two tumor suppressors that induce cellular senescence, p53 and p16(INK4a). Using primary mouse embryonic fibroblasts (MEFs), we show that c-Abl ( -/- ) cells were more resistant to immortalization than wildtype cells using a standard 3T3 or 3T9 protocol. We could only immortalize three out of nine c-Abl ( -/- ) MEF cultures even when we increased the number of starting cells. This resistance was attributed to premature senescence and reduced survival in senescent c-Abl ( -/- ) cells due to an increase in p16(INK4a) and p53 expression. Deleting p53 allows c-Abl ( -/- ) p53 ( -/- ) MEFs to bypass senescence to be spontaneously immortalized. Cell immortalization, but not senescence, was generally accompanied by mutations in p53 in both wildtype and c-Abl ( -/- ) MEFs, although the spectrum is different from that of human tumors. The role for c-Abl in regulating cell senescence and immortalization might explain some of the developmental defects in c-Abl ( -/- ) mice and how BCR-ABL transforms cells.
Authors:
Man Zhang; Lili Li; Zhongfeng Wang; Huijuan Liu; Junlin Hou; Min Zhang; Aijun Hao; Yun Liu; Guang He; Yongyong Shi; Lin He; Xueying Wang; Yue Wan; Baojie Li
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-13
Journal Detail:
Title:  Age (Dordrecht, Netherlands)     Volume:  -     ISSN:  1574-4647     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101250497     Medline TA:  Age (Dordr)     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Clinical Laboratory, Beijing Shi Ji Tan Hospital, Capital Medical University, Beijing, People's Republic of China.
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