PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway.
Identification and characterization of p53 target genes would lead to a better understanding of p53 functions and p53-mediated signaling pathways. Two putative p53 binding sites were identified in the promoter of a gene encoding PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member. Gel shift assay showed that p53 bound to both sites. Luciferase-coupled transactivation assay revealed that the gene promoter was activated in a p53 dose- as well as p53 binding site-dependent manner by wild-type p53 but not by several p53 mutants. The p53 binding and transactivation of the PTGF-beta promoter was enhanced by etoposide, a p53 activator, and was largely blocked by a dominant negative p53 mutant. Furthermore, expression of endogenous PTGF-beta was remarkably induced by etoposide in p53-positive, but not in p53-negative, cell lines. Finally, the conditioned medium collected from PTGF-beta-overexpressing cells, but not from the control cells, suppressed tumor cell growth. Growth suppression was not, however, seen in cells that lack functional TGF-beta receptors or Smad4, suggesting that PTGF-beta acts through the TGF-beta signaling pathway. Thus, PTGF-beta, a secretory protein, is a p53 target that could mediate p53-induced growth suppression in autocrinal as well as paracrinal fashions. The finding made a vertical connection between p53 and TGF-beta signaling pathways in controlling cell growth and implied a potential important role of p53 in inflammation regulation via PTGF-beta.
Tan
M
M
Department of Molecular Biology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Wang
Y
Y
Guan
K
K
Sun
Y
Y
D001665:Binding Sites; D002455:Cell Division; D002630:Chemotactic Factors / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D017930:Genes, Reporter; D005979:Glutathione Peroxidase / Q000235:genetics; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D011257:Pregnancy Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002630:Chemotactic Factors; D004268:DNA-Binding Proteins; D006133:Growth Substances; D011257:Pregnancy Proteins; D018125:Receptors, Transforming Growth Factor beta; D009418:S100 Proteins; C098997:S100A2 protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D005979:Glutathione Peroxidase