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J. Biol. Chem., Vol. 277, Issue 39, 36329-36337, September 27, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/39/36329    most recent M204962200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, Q. Articles by Liu, S. Search for Related Content PubMed PubMed Citation Articles by Wu, Q. Articles by Liu, S. Social Bookmarking                      What's this?

Transcriptional Regulation during p21^WAF1/CIP1-induced Apoptosis in Human Ovarian Cancer Cells^*

Qun Wu, Paul Kirschmeier, Tish Hockenberry, Tong-Yuan Yang^§, Diana L. Brassard^§, Luquan Wang^¶, Terri McClanahan, Stuart Black, Giovanni Rizzi^§, Mary Lynn Musco^§, Asra Mirza, and Suxing Liu^**

From the  Tumor Biology Department and ^¶ Human Genomic Research Department, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, ^§ Biotechnology Development, Schering-Plough Research Institute, Union, New Jersey 07083, and  DNAX Research Institute, Palo Alto, California 94304

In this study we used adenovirus vector-mediated transduction of either the p53 gene (rAd-p53) or the p21^WAF1/CIP1 gene (rAd-p21) to mimic both p53-dependent and -independent up-regulation of p21^WAF1/CIP1 within a human ovarian cancer cell line, 2774, and the derivative cell lines, 2774qw1 and 2774qw2. We observed that rAd-p53 can induce apoptosis in both 2774 and 2774qw1 cells but not in 2774qw2 cells. Surprisingly, overexpression of p21^WAF1/CIP1 also triggered apoptosis within these two cell lines. Quantitative reverse transcription-PCR analysis revealed that the differential expression of BAX, BCL2, and caspase 3 genes, specific in rAd-p53-induced apoptotic cells, was not altered in rAd-p21-induced apoptotic cells, suggesting p21^WAF1/CIP1-induced apoptosis through a pathway distinguishable from p53-induced apoptosis. Expression analysis of 2774qw1 cells infected with rAd-p21 on 60,000 cDNA microarrays identified 159 genes in response to p21^WAF1/CIP1 expression in at least one time point with 2.5-fold change as a cutoff. Integration of the data with the parallel microarray experiments with rAd-p53 infection allowed us to extract 66 genes downstream of both p53 and p21^WAF1/CIP1 and 93 genes in response to p21^WAF1/CIP1 expression in a p53-independent pathway. The genes in the former set may play a dual role in both p53-dependent and p53-independent pathways, and the genes in the latter set gave a mechanistic molecular explanation for p53-independent p21^WAF1/CIP1-induced apoptosis. Furthermore, promoter sequence analysis suggested that transcription factor E2F family is partially responsible for the differential expression of genes following p21^WAF1/CIP1. This study has profound significance toward understanding the role of p21^WAF1/CIP1 in p53-independent apoptosis.

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