Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways.
WAF1/Cip1 was recently identified as the wild-type p53 target that appears to mediate the tumor suppressing effects of p53. We investigated the mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma (HBC) cells. Our results demonstrate that the HBC cells harboring wild-type p53 express 26-33-fold higher WAF1/Cip1 mRNA levels than the cells harboring mutant p53. The DNA damaging agent etoposide induced p53 accumulation only in cells harboring wild-type p53 yet it induced WAF1/Cip1 gene expression in cells carrying wild-type or mutant p53, suggesting the involvement of p53-dependent and independent signaling pathways in the regulation of WAF1/Cip1 gene expression. Serum starvation-induced growth arrest although not altering the endogenous p53 levels or its ability to transactivate the reporter gene, induced WAF1/Cip1 gene expression in cells carrying wild-type as well as mutant p53. These results further implicated the involvement of p53-independent signal transduction pathways in WAF1/Cip1 gene regulation. Our data also suggest that WAF1/Cip1 gene expression is tightly associated with cell cycle progression in cells containing either wild-type or mutant p53. WAF1/Cip1 expression was transiently induced in response to serum treatment and declined as the cells passed through the S-phase of the cell cycle. We thus provide evidence that the mechanisms of WAF1/Cip1 gene regulation involve p53-dependent and independent signaling pathways in HBC.
Sheikh
M S
MS
Department of Medicine, University of Maryland School of Medicine, Baltimore.
Li
X S
XS
Chen
J C
JC
Shao
Z M
ZM
Ordonez
J V
JV
Fontana
J A
JA
D001943:Breast Neoplasms / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53