title: Uncoupling cancer mutations reveals critical timing of p53 loss in sarcomagenesis.
abstract: It is well accepted that cancer develops following the sequential accumulation of multiple alterations, but how the temporal order of events affects tumor initiation and/or progression remains largely unknown. Here, we describe a mouse model that allows for temporally distinct cancer mutations. By integrating a Flp-inducible allele of K-ras(G12D) with established methods for Cre-mediated p53 deletion, we were able to separately control the mutation of these commonly associated cancer genes in vitro and in vivo. We show that delaying p53 deletion relative to K-ras(G12D) activation reduced tumor burden in a mouse model of soft-tissue sarcoma, suggesting that p53 strongly inhibits very early steps of transformation in the muscle. Furthermore, using in vivo RNA interference, we implicate the p53 target gene p21 as a critical mediator in this process, highlighting cell-cycle arrest as an extremely potent tumor suppressor mechanism.
authors.affiliation: Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Young
authors.forename: Denise
authors.initials: D
authors.lastname: Crowley
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D011905:Genes, ras; D007150:Immunohistochemistry; D019426:Integrases / Q000235:genetics; D051379:Mice; D009154:Mutation; D012513:Sarcoma, Experimental / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*
chemical_list: C045073:Cre recombinase; D019426:Integrases