Identification of transcription enhancing fator for PTH receptor and analysis it's mechanism at jaw bone resorption site by oral cancer

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Parathyroid hormone (PTH) and PTH related protein (PTHrP) exert their effects on bone metabolism by binding to the G protein-coupled PTH/PTHrP receptor (PTH1R) expressed on osteoblasts. They increase expression of the osteoclast activating factor (RANKL) and enhance bone resorption.The rat, mouse and human PTH1R genes contain four 5' noncoding exons (Ul, U2, U3 and U4) and three promoter regions. A TATA-like promoter upstream of exon Ul is referred to as the P1 promoter and a GCrich promoter upstream of exon U3 and U4 is called the P2 and P3 promoters respectively. In rats, the downstream promoter (P2) was active in a variety of tissues including bone and kidney, while the upstream promoter (P1) was tissue-specific, showing activity in the kidney and the ovary.In the present study, we attempted to analyze the mechanism of transcription related factor(s) on the promoter P2 of the PTH1R in the rat osteoblasts and their mechanism at jaw bone resorption site by oral cancer.1.The core promo … More ter region (-128/+103) of the U3 promoter (P2) was composed of three important parts.(1)The +1/+12 region in the PTHSR (+11+25) fanctioned as an initiator (Inr) element. (2) The -128/-1 region fanctioned as an activator binding domain affected by MAZ and/or Sp1. (3) The +51/+103 region fanctioned as a downstream promoter element.2.The Inr element in the U3 promoter was recognized by specific protein(s). The PTH or IGF-I treatment decreased stability of that complex and attenuated the transcription activity ofPTH1R.3.Affinity purification revealed that the candidate protein(s) could bind to the PTHSR region were 112 and/or 129 kDa protein(s).4.In almost all of soft oral cancer tissues, the PTHrP expression markedly increased compared with the normal part. In the jaws adjacent to cancer tissues with high expression of PTI-IrP, one of the candidate protein expression did not decrease, but the PTH1 R expression downregulated. The bone metabolism marker such as RANKL and Cathepsin K were increased and OPG slightly decreased in this situation. Less