title: Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells.
abstract: A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53(R175H) mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53(R175H), was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53(R175H) mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53(R175H) mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Kogan-Sakin
authors.forename: Y
authors.initials: Y
authors.lastname: Tabach
authors.forename: Y
authors.initials: Y
authors.lastname: Buganim
authors.forename: A
authors.initials: A
authors.lastname: Molchadsky
authors.forename: H
authors.initials: H
authors.lastname: Solomon
authors.forename: S
authors.initials: S
authors.lastname: Madar
authors.forename: I
authors.initials: I
authors.lastname: Kamer
authors.forename: P
authors.initials: P
authors.lastname: Stambolsky
authors.forename: A
authors.initials: A
authors.lastname: Shelly
authors.forename: N
authors.initials: N
authors.lastname: Goldfinger
authors.forename: S
authors.initials: S
authors.lastname: Valsesia-Wittmann
authors.forename: A
authors.initials: A
authors.lastname: Puisieux
authors.forename: A
authors.initials: A
authors.lastname: Zundelevich
authors.forename: E N
authors.initials: EN
authors.lastname: Gal-Yam
authors.forename: C
authors.initials: C
authors.lastname: Avivi
authors.forename: I
authors.initials: I
authors.lastname: Barshack
authors.forename: M
authors.initials: M
authors.lastname: Brait
authors.forename: D
authors.initials: D
authors.lastname: Sidransky
authors.forename: E
authors.initials: E
authors.lastname: Domany
authors.forename: V
authors.initials: V
authors.lastname: Rotter
mesh_terms: D019943:Amino Acid Substitution; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C069077:BMI1 protein, human; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C103173:TWIST1 protein, human; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1; D063150:Polycomb Repressive Complex 1