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 hypercalcemia. Most of the actions of PTHrP have been attributed to its interaction with a specific cell surface receptor that binds the N-terminal domain of the protein. Here we present evidence that PTHrP promotes some of its cellular effects by translocating to the nucleolus. Localization of transiently expressed PTHrP to the nucleolus was dependent on the presence of a highly basic region at the carboxyl terminus of the molecule that bears homology to nucleolar targeting sequences identified within human retroviral (human immunodeficiency virus type 1 and human T-cell leukemia virus type 1) regulatory proteins. Endogenous PTHrP also localized to the nucleolus in osseous cells in vitro and in vivo. Moreover, expression of PTHrP in chondrocytic cells (CFK2) delayed 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 programmed cell death.
Henderson
J E
JE
Division of Endocrinology, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec, Canada.
Amizuka
N
N
Warshawsky
H
H
Biasotto
D
D
Lanske
B M
BM
Goltzman
D
D
Karaplis
A C
AC
D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D001692:Biological Transport; D002356:Cartilage / Q000166:cytology / Q000502:physiology*; D002451:Cell Compartmentation; D002466:Cell Nucleolus / Q000378:metabolism*; D002470:Cell Survival; D004249:DNA Damage; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D011994:Recombinant Proteins