A role for c-Abl in cell senescence and spontaneous immortalization.
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.
Department of Clinical Laboratory, Beijing Shi Ji Tan Hospital, Capital Medical University, Beijing, People's Republic of China.
Man
M
Zhang
Lili
L
Li
Zhongfeng
Z
Wang
Huijuan
H
Liu
Junlin
J
Hou
Min
M
Zhang
Aijun
A
Hao
Yun
Y
Liu
Guang
G
He
Yongyong
Y
Shi
Lin
L
He
Xueying
X
Wang
Yue
Y
Wan
Baojie
B
Li
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D016313:Genes, abl / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL / Q000196:embryology; D011247:Pregnancy; D011270:Pregnancy, Animal; D000090063:Proto-Oncogene Mas; D012313:RNA / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012313:RNA