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Molecular and Cellular Biology, April 2002, p. 1981-1992, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.1981-1992.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Stat1-Dependent, p53-Independent Expression of p21waf1 Modulates Oxysterol-Induced Apoptosis

Sudesh Agrawal,1 Munna L. Agarwal,2 Moitreyee Chatterjee-Kishore,2,{dagger} George R. Stark,2 and Guy M. Chisolm1*

Departments of Cell Biology,1 Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441952

Received 19 September 2001/ Returned for modification 20 November 2001/ Accepted 28 December 2001

7-Ketocholesterol (7kchol) is prominent in atherosclerotic lesions where apoptosis occurs. Using mouse fibroblasts lacking p53, p21waf1, or Stat1, we found that optimal 7kchol-induced apoptosis requires p21waf1 and Stat1 but not p53. Findings were analogous in a human cell system. Apoptosis was restored in Stat1-null human cells when wild-type Stat1 was restored. Phosphorylation of Stat1 on Ser727 but not Tyr701 was essential for optimum apoptosis. A neutralizing antibody against beta interferon (IFN-ß) blunted Ser727 phosphorylation and apoptosis after 7kchol treatment; cells deficient in an IFN-ß receptor subunit exhibited blunted apoptosis. IFN-ß alone did not induce apoptosis; thus, 7kchol-induced release of IFN-ß was necessary but not sufficient for optimal apoptosis. In Stat1-null cells, expression of p21waf1 was much less than in wild-type cells; introducing transient expression of p21waf1 restored apoptosis. Stat1 and p21waf1 were essential for downstream apoptotic events, including cytochrome c release from mitochondria and activation of caspases 9 and 3. Our data reveal key elements of the cellular pathway through which an important oxysterol induces apoptosis. Identification of the essential signaling events that may pertain in vivo could suggest targets for therapeutic intervention.

* Corresponding author. Mailing address: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation (NC-10), 9500 Euclid Ave., Cleveland, OH 44195. Phone: (216) 444-5854. Fax: (216) 444-9404. E-mail: chisolg{at}ccf.org.

{dagger} Present address: Genetics Institute, Cambridge, MA 02140.

Molecular and Cellular Biology, April 2002, p. 1981-1992, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.1981-1992.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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