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Molecular and Cellular Biology, July 2009, p. 3953-3963, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00449-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Stxbp4 Regulates {Delta}Np63 Stability by Suppression of RACK1-Dependent Degradation {triangledown}

Yingchun Li,{dagger} Melissa J. Peart, and Carol Prives*

Department of Biological Sciences, Columbia University, New York, New York 10027

Received 7 April 2009/ Returned for modification 20 April 2009/ Accepted 5 May 2009

p63, a member of the p53 tumor suppressor family, is essential for the development of epidermis as well as other stratified epithelia. Collective evidence indicates that {Delta}Np63 proteins, the N-terminally deleted versions of p63, are essential for the proliferation and survival of stratified epithelial cells and squamous cell carcinoma cells. But in response to DNA damage, {Delta}Np63 proteins are quickly downregulated in part through protein degradation. To elucidate the mechanisms by which {Delta}Np63 proteins are maintained at relatively high levels in proliferating cells but destabilized in response to stress, we sought to identify p63 interactive proteins that regulate p63 stability. We found that Stxbp4 and RACK1, two scaffold proteins, play central roles in balancing {Delta}Np63 protein levels. While Stxbp4 functions to stabilize {Delta}Np63 proteins, RACK1 targets {Delta}Np63 for degradation. Under normal growth conditions, Stxbp4 is indispensable for maintaining high basal levels of {Delta}Np63 and preventing RACK1-mediated p63 degradation. Upon genotoxic stress, however, Stxbp4 itself is downregulated, correlating with {Delta}Np63 destabilization mediated in part by RACK1. Taken together, we have delineated key mechanisms that regulate {Delta}Np63 protein stability in vivo.

* Corresponding author. Mailing address: Department of Biological Sciences, Columbia University, New York, NY 10027. Phone: (212) 854-2557. Fax: (212) 865-8246. E-mail: clp3{at}columbia.edu

{triangledown} Published ahead of print on 18 May 2009.

{dagger} Present address: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064.

Molecular and Cellular Biology, July 2009, p. 3953-3963, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00449-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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