title: Therapeutic efficacy of p53 restoration in Mdm2-overexpressing tumors.
abstract: The p53 (TP53) tumor suppressor is the most frequently mutated gene in human cancers. Restoring expression of wild-type p53 has led to tumor growth suppression in a variety of tumor models that are p53 deficient. Other mechanisms, for example, upregulation of Mdm2, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type p53. In this study, the effects of restoring p53 activity were probed in Mdm2-overexpressing tumors genetically using animal models. Here, it was demonstrated that elevated levels of Mdm2 and decreased levels of p53 act additively to dampen p53 activity in DNA damage response and tumor development. Our data further indicate that restoration of wild-type p53 expression in Mdm2-overexpressing angiosarcomas results in tumor stasis and regression in some cases. Finally, it was determined that restored p53 suppressed cell proliferation but did not elicit apoptosis in the Mdm2-overexpressing angiosarcomas.
  
  
  CONCLUSIONS
  Restoration of wild-type p53 expression in Mdm2-overexpressing tumors suppresses tumor growth, which represents a potential clinical strategy to treat tumors with high levels of Mdm2.
authors.affiliation: Authors' Affiliations: Department of Genetics, Program in Genes and Development, Graduate School of Biomedical Sciences, and.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Department of Genetics.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Authors' Affiliations: Department of Genetics.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Authors' Affiliations: Department of Genetics.
authors.forename: Peirong
authors.initials: P
authors.lastname: Yang
authors.affiliation: Authors' Affiliations: Department of Genetics.
authors.forename: James G
authors.initials: JG
authors.lastname: Jackson
authors.affiliation: Authors' Affiliations: Department of Genetics.
authors.forename: Gilda
authors.initials: G
authors.lastname: Chau
authors.affiliation: Authors' Affiliations: Department of Genetics, gglozano@mdanderson.org.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006394:Hemangiosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2