| Parathyroid hormone (PTH) is an 84 amino acid polypeptide hormone which has both catabolic and anabolic effects in skeletal tissue and in vitro. Most of the catabolic actions of PTH are protein kinase A (PKA) dependent and some of the changes in gene expression are mediated by the cAMP response element binding protein (CREB). Serines 129 and 133 of CREB were determined to be absolutely required for CREB transactivation, and are phosphorylated by glycogen synthase kinase-3β (GSK-3β) and protein kinase A, respectively. Additionally, epidermal growth factor (EGF) transactivates CREB alone via extracellular-signal regulated kinases (ERKs) and p38 mitogen activated protein kinase, or synergistically with PTH. Furthermore, both serines 129 and 133 are required for EGF-induced transcriptional activity.; It is believed that many of the anabolic actions of PTH are mediated by protein kinase C (PKC). In osteoblasts, continuous treatment with an anabolic concentration of PTH or PTH peptides, which selectively activate PKC, results in significant increases in growth, DNA synthesis, and activation of ERKs. ERK activation occurs independently of tyrosine phosphorylation of the EGF receptor, Ras activation, or βγ subunits. Furthermore, the mRNA and protein levels for cyclin E are induced with anabolic concentrations of PTH and activity of the cyclin E dependent kinase, Cdk2, increases. The mRNA levels for the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 are elevated basally and remain high throughout the cell cycle, however p21CiP1 protein levels decrease following treatment with an anabolic concentration of PTH, likely a consequence of ubiquitination and subsequent degradation. Finally, microarray analysis yielded many genes previously unknown to be regulated by PTH and one EST regulated by anabolic concentrations of PTH and which was dependent upon ERKs. In addition to ERK activation and regulation of components of the cell cycle, analysis of this EST may yield new insights into the anabolic actions of PTH. |
