JBC INTERFERin siRNA transfection reagent

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Papers In Press, published online ahead of print May 6, 2004
J. Biol. Chem, 10.1074/jbc.M404651200
Submitted on April 27, 2004
Revised on May 5, 2004
Accepted on May 6, 2004

Casein kinase 1alpha interacts with retinoid X receptor and interferes with agonist-induced apoptosis

Yi Zhao, Suofu Qin, Larissa I. Atangan, Yanira Molina, Yumiko Okawa, Hieu T. Arpawong, Corine Ghosn, Jia-Hao Xiao, Vidyasagar Vuligonda, Geoffrey Brown, and Roshantha A.S. Chandraratna

Retinoid Reseach, Department of Biological Sciences, Allergan Inc., Irvine, CA 92612

Corresponding Author: zhao_yi{at}allergan.com

Agonists of retinoid X receptors (RXRs), that include the natural 9-cis retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anti-cancer effects of RXR agonists remain unclear. Here, we show that a novel pro-apoptotic pathway that is induced by RXR agonist is negatively regulated by casein kinase 1 alpha (CK1alpha ). CK1alpha associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of a RXR agonist to recruit CK1alpha to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1alpha in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1alpha can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1alpha may enhance the anti-cancer effects of RXR agonists.


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