title: P53 is transported into the nucleus via an Hsf1-dependent nuclear localization mechanism.
abstract: Loss of p53 function can occur through disruption of its ability to localize to the nucleus. Previously we showed through characterization a set of mutant cell lines that lacked the ability to import p53 into the nucleus that nuclear translocation of p53 appeared to be mechanistically different from that of the SV40 T-antigen (SV40TAg). Here we extend that work by examining nuclear importation of p53 and SV40TAg using both in vivo and in vitro assays for nuclear localization. We show that disruption of microtubule polymerization using colchicine suppresses nuclear localization of p53 but not of SV40TAg. We also show, for the first time, that the heat shock transcription factor (Hsf1), is required for establishment of the microtubule network in cells and for nuclear localization of p53. In contrast, SV40TAg does not interact with polymerized microtubules suggesting that it is transported into the nucleus through an alternative mechanism. Interestingly, lacking of Hsf1 expression and suppressing Hsf1 by siRNA also made cells more resistant to the cytotoxic effects of paclitaxel. Hence, loss of Hsf1 activity not only suppressed p53 function, but also led to reduced sensitivity to killing by drugs that target microtubules.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Martinez
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D000076249:Heat Shock Transcription Factors; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D014157:Transcription Factors; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D003078:Colchicine