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Molecular and Cellular Biology, December 2000, p. 9271-9280, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

v-Src Generates a p53-Independent Apoptotic Signal

Brian L. Webb, Elsa Jimenez, and G. Steven Martin*

Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720

Received 5 May 2000/Returned for modification 20 June 2000/Accepted 25 September 2000

Evasion of apoptosis appears to be a necessary event in tumor progression. Some oncogenes, such as c-myc and E1A, induce apoptosis in the absence of survival factors. However, others, such as bcl-2 and v-src, activate antiapoptotic pathways. For v-Src, these antiapoptotic pathways are dependent on the function of Ras, phosphatidylinositol (PI) 3-kinase, and Stat3. Here we asked whether v-Src can activate a proapoptotic signal when survival signaling is inhibited. We show that when the functions of Ras and PI 3-kinase are inhibited, v-src-transformed Rat-2 fibroblasts undergo apoptosis, evidenced by loss of adherence, nuclear fragmentation, and chromosomal DNA degradation. The apoptotic response is dependent on activation of caspase 3. Under similar conditions nontransformed Rat-2 cells undergo considerably lower levels of apoptosis. Apoptosis induced by v-Src is accompanied by a loss of mitochondrial membrane potential and release of cytochrome c and is blocked by overexpression of bcl-2, indicating that it is mediated by the mitochondrial pathway. However apoptosis induced by v-Src is not accompanied by an increase in the level of p53 and is not dependent on p53 function. Thus v-Src generates a p53-independent proapoptotic signal.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, University of California at Berkeley, 401 Barker Hall #3204, Berkeley, CA 94720-3204. Phone: (510) 642-1508. Fax: (510) 643-1729. E-mail: smartin{at}socrates.berkeley.edu.

Molecular and Cellular Biology, December 2000, p. 9271-9280, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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