Regulation of PT proliferation, gene expression, and secretion. Cyclin D1 driven by the PTH promoter and activating mutations of the Menin gene can both cause PT adenomas; germ-line mutations of the latter cause MEN 1. PT carcinomas, which are rare, show lack of expression of the retinoblastoma protein (pRb). Activating mutations of the RET proto-oncogene result in MEN 2a. A low serum calcium leads to a decreased activation of the CaSR and results in increased PTH secretion (blue dots), PTH mRNA stability and PT cell proliferation. A high serum phosphate leads to similar changes in each of these parameters. Endothelin and TGF-α are increased in the PTs of proliferating PT glands. 1,25(OH)2D3 decreases PTH gene transcription markedly and decreases PT cell proliferation. PTH mRNA stability is regulated by PT cytosolic proteins (trans factors, shown here in brown), which bind a short, defined cis sequence (pink) in the PTH mRNA 3′-UTR, preventing degradation by ribonucleases (red). One such protective protein is AUF1. In hypocalcemia, there is more binding of the trans factors to the cis sequence leading to a more stable transcript. A low serum phosphate leads to decreased binding and a rapidly degraded PTH transcript.