p53 controls hPar1 function and expression.
Human protease-activated receptor 1 (hPar1) is a bona fide receptor of the hemostatic protease thrombin, and has a central function in tumor progression. Inactivation of the tumor suppressor gene p53 is one of the most common genomic alterations occurring in cancer. Here, we address the interrelations between p53 and hPar1 in cancer. We demonstrate an inverse correlation between hPar1 gene expression and wild-type (wt) p53 levels, and a direct correlation with levels of the mutant (mt) p53. Bioinformatic search revealed the presence of at least two p53 motifs in the hPar1 promoter. Indeed, temperature-sensitive (ts) p53 forms reduced hPar1 promoter activity on wt p53 expression. Ectopic introduction of the p53R175H mutant into cells lacking p53 caused a moderate two-fold induction of hPar1 promoter activity. Chromatin immunoprecipitation (ChIP) analyses confirmed a physical association between the p53 protein and hPar1 chromatin fragments. In parallel, PAR1 function is attenuated by p53, as shown by inhibition of pFAK levels and a Matrigel invasion assay. Ectopic reinforcement of hPar1 rescued the inhibition conferred by p53, confirming that p53 directly affects hPar1 expression and function. Altogether, we provide evidence for a direct binding between p53 and hPar1 chromatin, and assign hPar1 as a target of p53.
Salah
Z
Z
Department of Oncology, Hadassah-University Medical Center, Jerusalem, Israel.
Haupt
S
S
Maoz
M
M
Baraz
L
L
Rotter
V
V
Peretz
T
T
Haupt
Y
Y
Bar-Shavit
R
R
D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D019295:Computational Biology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D044463:Receptor, PAR-1 / Q000235:genetics / Q000502:physiology*; D013489:Suppression, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D002843:Chromatin; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D016159:Tumor Suppressor Protein p53