title: Restoration of p53 function leads to tumour regression in vivo.
abstract: Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance; this phenotype is referred to as oncogene addiction. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.
authors.affiliation: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ventura
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Jan
authors.initials: J
authors.lastname: Grimm
authors.forename: Laura
authors.initials: L
authors.lastname: Lintault
authors.forename: Jamie
authors.initials: J
authors.lastname: Newman
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Reczek
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D016922:Cellular Senescence; D004195:Disease Models, Animal; D006801:Humans; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53