Parathyroid hormone (PTH) plays a central role in the regulation of serum
calcium and
phosphorus homeostasis, while
parathyroid hormone-related protein (
PTHrP) has important developmental roles. Both
peptides signal through the same
G protein-coupled receptor, the PTH/
PTHrP or PTH type 1 receptor (PTH1R).
PTHrP, normally a secreted
protein, also contains a
nuclear localization signal (NLS) that in vitro imparts functionality to the
protein at the level of the nucleus. We investigated this functionality in vivo by introducing a
premature termination codon in
Pthrp in ES cells and generating mice that express
PTHrP (1-84), a truncated form of the
protein that is missing the NLS and the C-terminal region of the
protein but can still signal through its
cell surface receptor. Mice homozygous for the knock-in mutation (
Pthrp KI) displayed retarded growth, early senescence, and
malnutrition leading postnatally to their rapid demise. Decreased cellular proliferative capacity and increased apoptosis in multiple tissues including bone and bone marrow cells were associated with altered expression and subcellular distribution of the senescence-associated
tumor suppressor proteins p16(INK4a) and p21 and the oncogenes
Cyclin D, pRb, and Bmi-1. These findings provide in vivo experimental proof that substantiates the
biologic relevance of the NLS and C-terminal portion of
PTHrP, a
polypeptide ligand that signals mainly via a cell surface
G protein-coupled receptor.