title: Expression of a dominant negative heat shock factor-1 construct inhibits aneuploidy in prostate carcinoma cells.
abstract: Recent studies have implicated heat shock proteins (HSP) and heat shock transcription factor 1 (HSF1) in tumor progression. We have examined the role of HSF1 in the malignant phenotype of PC-3 prostate carcinoma cells. We have developed a dominant negative construct of HSF1 that antagonizes transcription from HSP promoters and results in the depletion of intracellular HSP 70. Our studies indicate that expression of DN-HSF1 dramatically alters the DNA content of PC-3 cells (derived from p53 null prostatic carcinoma) and inhibits aneuploidy in these cells. This effect is due to prolonged expression of DN-HSF1, and transient expression of the dominant negative factor from an inducible promoter failed to cause the effect. Inhibition of aneuploidy in p53 null PC-3 cells by DN-HSF1 expression was recapitulated by expression within the cells of wild type p53. Furthermore, cells expressing DN-HSF1 showed a profound inhibition in the development of aneuploidy when exposed to chemical agents that disrupt the mitotic spindle and prevent progression through metaphase. Inhibition of aneuploidy in PC-3 cells expressing DN-HSF1 was associated with delayed breakdown of cyclin B1 compared with controls, consistent with a role for wild type HSF1 in the regulation of cyclin B1 degradation, a key step in the control of mitosis. Our experiments therefore demonstrate that HSF1 plays a functional role in cancer cells under nonstress conditions and influences cell cycle behavior and progression through mitosis and promotes the development of the aneuploid state.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Wang
authors.forename: Jimmy R
authors.initials: JR
authors.lastname: Theriault
authors.forename: Haiying
authors.initials: H
authors.lastname: He
authors.forename: Jianlin
authors.initials: J
authors.lastname: Gong
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Calderwood
mesh_terms: D000782:Aneuploidy; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D003703:Demecolcine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005799:Genes, Dominant; D017930:Genes, Reporter; D016158:Genes, p53; D005822:Genetic Vectors; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008938:Mitosis; D009154:Mutation; D010641:Phenotype; D011003:Ploidies; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*; D017434:Protein Structure, Tertiary; D016192:Resting Phase, Cell Cycle; D013050:Spectrometry, Fluorescence; D014157:Transcription Factors; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D050884:HSP72 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases; D003703:Demecolcine