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- W4384698855 abstract "Abstract PTHrP (Parathyroid Hormone-Related Protein) is a proteinaceous hormone and its signalling and functional regions are believed to be essential regulators for development for bone. Here, we report OSE2 element and PTH1R/PKA -independent physiology PTHrP C-terminus functions in bone. Using genetic models, we systematically interrogated PTHrP regions in various backgrounds in gene regulation, conducted on Ocy454 osteocytes overexpressing full-length PTHrP (Ocy454 PTHrP FL ), and mutant forms of PTHrP (Ocy454 PTHrP ΔNLSΔC , Ocy454 PTHrP ΔNLS , Ocy454 PTHrP ΔSec ). PTHrP C-terminus, but not the PTHrP-NLS, remarkably limits magnitude- and numbers- dependencies of PTH/PTHrP signalling activated genes in osteocytes and osteoblastic-like osteosarcoma. C-terminus plays protective effects in bone formation signaling by down-regulation of Bglap1/2 , observed in PTH /PTHrP signaling driven signalings. Unexpectedly, C-terminus gene suppression effect is cytosolic and is not dependent on canonical PTHrP-cAMP/PKA promoted signalling, nor is regulated by phosphorylated Runx2 binding to the OSE2 cis-regulatory elements. Instead, we show that PTHrP C-terminus mediated Bglap reduction results from stimulating Wnt signalling through an inhibition of Wnt inhibitor Dkk1. Collectively, our work identifies non-canonical PKA/cAMP/CREB response-independent functions of cytosolic PTHrP C-terminus to suppress Bglap, and unravel its complex endegenous C-terminus region-PTHrP interactions role in bone." @default.
- W4384698855 created "2023-07-20" @default.
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- W4384698855 date "2023-07-18" @default.
- W4384698855 modified "2023-10-18" @default.
- W4384698855 title "Endogenous PTHrP C-terminus antagonises Bglap towards a non-canonical pathway by stimulating Wnt signalling independently of OSE2 element and PTH1R/PKA signalling" @default.
- W4384698855 doi "https://doi.org/10.21203/rs.3.rs-3104562/v1" @default.
- W4384698855 hasPublicationYear "2023" @default.
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