Retrovirally mediated wild-type p53 restores S-phase modulation without inducing WAF1 mRNA in breast carcinoma cells containing mutant p53.
The mechanism of negative growth regulation by the nuclear phosphoprotein p53 in breast cancer cells may rely on its role as a transcriptional activator of cell cycle-related genes. We have tested this hypothesis using retrovirally transduced wild-type (wt) p53 in breast cancer cell lines containing homozygously endogenous mutant (mt) p53. Restoring the expression of wt p53, the percentage of cells in S phase was reduced, G1/S transition was slowed, and progression through S was restrained. The fraction of cells with a flattened "Cdk-minus" phenotype increased 5- to 10-fold. High constitutive mRNA expression of the cyclin-Cdk inhibitor WAF1 in MDAMB231 cells was not induced upon restored wt p53 expression suggesting a p53-independent pathway in the regulation of WAF1 mRNA expression. Wt p53 acted trans-dominantly in the presence of accumulating mt p53 and installed a modulation of G1/S transition and S phase progression independent of WAF1 expression.
Runnebaum
I B
IB
Department of Obstetrics and Gynecology, University of Ulm, Germany.
Wang
S
S
Kreienberg
R
R
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics*; D016196:S Phase; D014161:Transduction, Genetic; 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; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53