Journal article

Tolerance to sustained activation of the cAMP/Creb pathway activity in osteoblastic cells is enabled by loss of p53

Mannu K Walia, Scott Taylor, Patricia WM Ho, T John Martin, Carl R Walkley

Cell Death and Disease | NATURE PUBLISHING GROUP | Published : 2018

Abstract

The loss of p53 function is a central event in the genesis of osteosarcoma (OS). How mutation of p53 enables OS development from osteoblastic lineage cells is poorly understood. We and others have reported a key role for elevated and persistent activation of the cAMP/PKA/Creb1 pathway in maintenance of OS. In view of the osteoblast lineage being the cell of origin of OS, we sought to determine how these pathways interact within the context of the normal osteoblast. Normal osteoblasts (p53 WT) rapidly underwent apoptosis in response to acute elevation of cAMP levels or activity, whereas p53-deficient osteoblasts tolerated this aberrant cAMP/Creb level and activity. Using the p53 activating sm..

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Grants

Awarded by NHMRC


Awarded by Victorian Cancer Agency Mid-Career Research Fellowship (CRW)


Funding Acknowledgements

We thank the SVH BioResources Centre for animal care. This work was supported by grants: NHMRC Project Grant APP1084230 (to C.W., M.W., and T.J.M.); Victorian Cancer Agency Mid-Career Research Fellowship (CRW; MCRF15015); in part by the Victorian State Government Operational Infrastructure Support Program (to St. Vincent's Institute).