Mm. Aarts et al., Parathyroid hormone-related protein promotes quiescence and survival of serum-deprived chondrocytes by inhibiting rRNA synthesis, J BIOL CHEM, 276(41), 2001, pp. 37934-37943
Parathyroid hormone-related protein (PTHrP) was initially recognized for it
s ability to promote parathyroid hormone-like bioactivity in kidney, bone,
and squamous epithelial cells. PTHrP is a multifunctional protein in which
bioactivity is mediated by two distinct pathways. Its classic parathyroid h
ormone-like activity results from binding of its amino terminus to cell sur
face PTH1R and activation of signal transduction pathways. Another less wel
l recognized pathway involves translocation of PTHrP to the nucleus via a m
id-region bipartite nuclear targeting sequence (NTS), similar in structure
and function to those found in retroviral regulatory proteins. PTHrP was id
entified in the nucleus of several different cell types in vivo and in vitr
o, where it has been implicated in cell cycle progression, cellular differe
ntiation, and apoptosis. In previous work we showed that nuclear translocat
ion of PTHrP enhanced the survival of serum-deprived chondrogenic cells, as
sociated with RNA, and localized to a region of the nucleus rich in complex
es of newly transcribed ribosomal RNA and protein. In this work we have use
d two chondrogenic cell lines, CFK2 (PTH1R+) and 27m21 (PTH1R-) to further
explore mechanisms whereby PTHrP rescues immature chondrocytes from apoptos
is. Endogenous PTHrP and exogenous PTHrP NTS peptide protected serum-depriv
ed cells from apoptosis, in the presence and absence of PTH1R. The survival
of cells expressing PTHrP and those treated with PTHrP NTS peptide was ass
ociated with a rapid shift into G(o)/G(1) accompanied by a significant down
-regulation of rRNA synthesis and a decrease in the number of actively tran
slating polyribosome complexes. Together with our previous observations, th
is work predicts a role for PTHrP in modulating ribosome biogenesis and pre
venting chondrogenic cells from progressing through the cell cycle in an un
favorable environment.