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Type: Journal article
Title: Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance
Author: Walia, M.
Ho, P.
Taylor, S.
Ng, A.
Gupte, A.
Chalk, A.
Zannettino, A.
Martin, T.
Walkley, C.
Citation: eLife, 2016; 5(2016):e13446-1-e13446-31
Publisher: ELife Sciences Publications
Issue Date: 2016
ISSN: 2050-084X
Statement of
Mannu K Walia, Patricia MW Ho, Scott Taylor, Alvin JM Ng, Ankita Gupte, Alistair M Chalk, Andrew CW Zannettino, T John Martin, Carl R Walkley
Abstract: Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.
Keywords: Osteosarcoma;
Rights: © 2016, Walia et al This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
RMID: 0030047965
DOI: 10.7554/eLife.13446
Grant ID:
Appears in Collections:Medicine publications

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