title: Multiple stress signals activate mutant p53 in vivo.
abstract: p53 levels are tightly regulated in normal cells, and thus, the wild-type p53 protein is nearly undetectable until stimulated through a variety of stresses. In response to stress, p53 is released from its negative regulators, mainly murine double minute 2 (Mdm2), allowing p53 to be stabilized to activate cell-cycle arrest, senescence, and apoptosis programs. Many of the upstream signals that regulate wild-type p53 are known; however, limited information for the regulation of mutant p53 exists. Previously, we showed that wild-type and mutant p53R172H are regulated in a similar manner in the absence of Mdm2 or p16. In addition, this stabilization of mutant p53 is responsible for the gain-of-function metastatic phenotype observed in the mouse. In this report, we examined the role of oncogenes, DNA damage, and reactive oxygen species, signals that stabilize wild-type p53, on the stabilization of mutant p53 in vivo and the consequences of this expression on tumor formation and survival. These factors stabilized mutant p53 protein which oftentimes contributed to exacerbated tumor phenotypes. These findings, coupled with the fact that patients carry p53 mutations without stabilization of p53, suggest that personalized therapeutic schemes may be needed for individual patients depending on their p53 status.
authors: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Young-Ah
authors: YA
authors: Suh
authors: Sean M
authors: SM
authors: Post
authors: Ana C
authors: AC
authors: Elizondo-Fraire
authors: Daniela R
authors: DR
authors: Maccio
authors: James G
authors: JG
authors: Jackson
authors: Adel K
authors: AK
authors: El-Naggar
authors: Carolyn
authors: C
authors: Van Pelt
authors: Tamara
authors: T
authors: Terzian
authors: Guillermina
authors: G
authors: Lozano
mesh_terms: D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004249:DNA Damage; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D011905:Genes, ras; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2