Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein.
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.
Miao
Dengshun
D
Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Su
Hanyi
H
He
Bin
B
Gao
Jianjun
J
Xia
Qingwen
Q
Zhu
Min
M
Gu
Zhen
Z
Goltzman
David
D
Karaplis
Andrew C
AC
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D049109:Cell Proliferation; D055879:Gene Knock-In Techniques; D006130:Growth Disorders / Q000209:etiology* / Q000235:genetics; D044342:Malnutrition / Q000209:etiology / Q000235:genetics; D051379:Mice; D050505:Mutant Proteins; D019913:Nuclear Localization Signals / Q000172:deficiency*; D009857:Oncogenes; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000502:physiology*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins
D050505:Mutant Proteins; D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein; D025521:Tumor Suppressor Proteins