NUCLEOLAR LOCALIZATION OF PARATHYROID HORMONE-RELATED PEPTIDE ENHANCES SURVIVAL OF CHONDROCYTES UNDER CONDITIONS THAT PROMOTE APOPTOTIC CELL-DEATH

Parathyroid hormone-related peptide (PTHrP) is a mediator of cellular growth and differentiation as well as a cause of malignancy-induced hy percalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-ter minal domain of the protein. Here we present evidence that PTHrP promo tes some of its cellular effects by translocating to the nucleolus. Lo calization of transiently expressed PTHrP to the nucleolus was depende nt on the presence of a highly basic region at the carboxyl terminus o f the molecule that bears homology to nucleolar targeting sequences id entified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenou s PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) de layed apoptosis induced by serum deprivation, and this effect depended on the presence of an intact nucleolar targeting signal. The present findings demonstrate a unique intracellular mode of PTHrP action and a novel mechanism by which this peptide growth factor may modulate prog rammed cell death.