Tumor suppressor p53 regulates heparanase gene expression.
Mammalian heparanase degrades heparan sulfate, the most prominent polysaccharide of the extracellular matrix. Causal involvement of heparanase in tumor progression is well documented. Little is known, however, about mechanisms that regulate heparanase gene expression. Mutational inactivation of tumor suppressor p53 is the most frequent genetic alteration in human tumors. p53 is a transcription factor that regulates a wide variety of cellular promoters. In this study, we demonstrate that wild-type (wt) p53 binds to heparanase promoter and inhibits its activity, whereas mutant p53 variants failed to exert an inhibitory effect. Moreover, p53-H175R mutant even activated heparanase promoter activity. Elimination or inhibition of p53 in several cell types resulted in a significant increase in heparanase gene expression and enzymatic activity. Trichostatin A abolished the inhibitory effect of wt p53, suggesting the involvement of histone deacetylation in negative regulation of the heparanase promoter. Altogether, our results indicate that the heparanase gene is regulated by p53 under normal conditions, while mutational inactivation of p53 during cancer development leads to induction of heparanase expression, providing a possible explanation for the frequent increase of heparanase levels observed in the course of tumorigenesis.
Department of Oncology, Hadassah-University Medical Center, Jerusalem, Israel.
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L
Baraz
Y
Y
Haupt
M
M
Elkin
T
T
Peretz
I
I
Vlodavsky
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005966:Glucuronidase / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000099175:Heparanase
D017931:DNA Primers; D005966:Glucuronidase; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; D000099175:Heparanase; C495901:TP53 protein, human; C012589:trichostatin A