Genomic instability due to germline p53 mutations drives preneoplastic progression toward cancer in human cells.
Cells heterozygous for mutations in p53 demonstrate extreme genomic instability and develop mutations detectable at the chromosome level as well as the molecular level. This genomic instability causes initially nontumorigenic ras-expressing immortal LFS cells to progress to a tumorigenic state presumably due to additional mutational events. It is not surprising that LFS families with these p53 mutations develop the additional mutations necessary for cancer to occur at such high frequencies. This observation is consistent with increased cancer rates in these families being due to abrogation of a rate limiting step rather than a rate expected for one less step in a multistep carcinogenic process. Although p53 has been shown to be able to function as a transcription factor, mutations in p53 appear to affect genomic stability in LFS fibroblasts with double minutes and telomeric associations being prominent early events. One possibility is that p53 controls the expression of genes required for fidelity of replication or telomerase activity. Alternatively p53 may itself be a replication factor like the transcription factor CTF. In the future, we plan to investigate whether p53 plays a direct role in replication.
Tainsky
M A
MA
Department of Tumor Biology, University of Texas, M.D. Anderson Cancer Center, Houston, USA.
Bischoff
F Z
FZ
Strong
L C
LC
D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D011905:Genes, ras / Q000502:physiology; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D017354:Point Mutation; D011230:Precancerous Conditions / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
D016159:Tumor Suppressor Protein p53