The temperature sensitive mutant p53-143ala extends in vitro life span, promotes errors in DNA replication and impairs DNA repair in normal human oral keratinocytes.
Many human cancers contain a hemizygous point missense mutation in p53, allowing expression of both wild-type and mutant p53. To understand the relationship between wild-type and mutant p53 in cells, we investigated the influence of a naturally occurring temperature-sensitive mutant p53 (valine to alanine substitution at codon 143: mp53-143ala) on the life span of normal human oral keratinocytes (NHOK) and the expression of wild-type p53. We also investigated the effect of the mutant p53 on the genetic stability of NHOK. The mp53-143ala extended the in vitro life span of NHOK by four-fold, but failed to overcome the M2 crisis stage for immortalization. The mp53-143ala notably suppressed wild-type p53 in NHOK at post-transcriptional levels. Moreover, the mp53-143ala notably increased both spontaneous and genotoxic agent-induced mutation frequency of a shuttle vector in NHOK. These data indicate that mutant p53 induces genetic instability by, in part, inhibiting the expression of wild-type p53 through a dominant negative role in cells expressing both mutant and wild-type p53.
Liu
X
X
UCLA School of Dentistry and Dental Research Institute, Los Angeles, CA 90095, USA.
Nishitani
J
J
McQuirter
J L
JL
Baluda
M A
MA
Park
N H
NH
D016923:Cell Death; D002455:Cell Division; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D004261:DNA Replication; D005434:Flow Cytometry; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D009055:Mouth / Q000166:cytology; D016296:Mutagenesis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53