Parathyroid hormone-related protein (PTHrP) is expressed in many tissues and is often enriched in cancers. Tissue reaction to PTHrP varies as it is expressed as multiple isoforms, undergoes peptide processing, and has selective trafficking. PTHrP is secreted via a pre-pro -36 to -1 amino acid portion and interacts with extracellular receptors, including parathyroid hormone receptor 1 (PTH1R). PTHrP is also present within the cell and shuttles into and out of the nucleus via a nuclear localization signal (NLS) and a nuclear export signal (NES). Patients diagnosed with non-small cell lung carcinomas that express PTHrP, experience higher survival rates. PTHrP's benefits in non-small cell lung cancer may result from its previously demonstrated anti-proliferative effects. Because of PTHrP's highly intricate actions, its site of inhibitory action on proliferation is not known. This project experimentally isolated the site of action and likely receptor responsible for PTHrP's inhibition on H1944 cells, an adenocarcinoma cell line. Early experimental results suggested that exogenous PTHrP has at least a partial role in growth inhibition. We successfully demonstrated that the nuclear trafficking of PTHrP is not necessary for inhibition of proliferation. We showed that PTHrP peptide introduced into the cell has no major effects on proliferation. Finally, we demonstrated that exogenous PTHrP treatments have the potential to inhibit proliferation at levels near stably transfected lines and that PTHrP does not inhibit cells with PTH1R knocked down. Based on these results we conclude that PTHrP inhibits proliferation of H1944 cells in an extracellular fashion dependent on the PTH1R

The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of β-catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease.