Casein Kinase 1α Interacts with Retinoid X Receptor and Interferes with Agonist-induced Apoptosis

Abstract

Agonists of retinoid X receptors (RXRs), which 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 anticancer 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␣ (CK1␣). CK1␣ associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an RXR agonist to recruit CK1␣ to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1␣ in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1␣ can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1␣ may enhance the anti-cancer effects of RXR agonists.

Phosphorylation by Casein Kinase 1 Regulates Tonicity-induced Osmotic Response Element-binding Protein/Tonicity Enhancer-binding Protein Nucleocytoplasmic Trafficking

“…As a result, CK1 regulates numerous cellular process such as cell cycle progression and cytokinesis (56), chromosome and microtubule dynamics (57,58), circadian rhythm (51), and apoptosis (59,60). CK1 is also known to regulate the subcellular localization of transcription factors.…”

Analysis of Cell Type-specific Expression of CK1ε in Various Tissues of Young Adult BALB/c Mice and in Mammary Tumors of SV40 T-Ag-transgenic Mice

“…Members of the CK1 family are found in the nucleus, the cytoplasm, and in the plasma membrane (reviewed in Gross and Anderson 1998;Knippschild et al 2005). By phosphorylating many different substrates bearing either a canonical or non-canonical consensus sequence (Gross and Anderson 1998;Marin et al 2003;Okamura et al 2004b;Bustos et al 2005), they modulate the activity of key regulator proteins involved in many cellular processes, such as cell differentiation (Peters et al 1999;Amit et al 2002;Liu et al 2002;Davidson et al 2005;Zeng et al 2005;Swiatek et al 2006), cell proliferation, apoptosis (Beyaert et al 1995;Desagher et al 2001;Izeradjene et al 2004;Takenaka et al 2004;Zhao et al 2004), circadian rhythm (Camacho et al 2001), chromosome segregation (Brockman et al 1992;Behrend et al 2000a,b;Petronczki et al 2006), and vesicle transport (Brockman et al 1992;Milne et al 2001;Behrend et al 2000b). Because CK1 is involved in so many different cellular processes, mutations and/ or changes in the activity of CK1 isoforms have a great impact on the development of several diseases, including neurodegenerative diseases (Kuret et al 1997;Walter et al 1998;Schwab et al 2000;Yasojima et al 2000;Ebisawa et al 2001;Toh et al 2001;Takano et al 2004;Xu et al 2005) and cancer (Elias et al 1981;Maritzen et al 2003;Bagheri-Yarman...…”

Protein Kinase CK1α Regulates mRNA Binding by Heterogeneous Nuclear Ribonucleoprotein C in Response to Physiologic Levels of Hydrogen Peroxide

“…Although some members of the CK1 family, such as CK1␦ and CK1⑀, are activated by dephosphorylation of inhibitory autophosphorylation sites (38 -40), this mechanism appears not to apply to CK1␣, which is typically isolated in the fully active form. It is possible that CK1␣-mediated phosphorylation may be regulated by sequestration of the kinase into specific complexes via protein-protein interactions (41,42). Such an activation mechanism may help to explain some of the paradoxical actions of this kinase.…”

“…Such an activation mechanism may help to explain some of the paradoxical actions of this kinase. For example, protein kinase CK1␣ has been observed to be a positive regulator of cell cycle progression (43), to promote cell survival by inhibiting retinoid X receptor-induced growth arrest and apoptosis (42), and to promote mitogenic signaling from m3 muscarinic acetylcholine receptors (44). However, CK1␣ has also been demonstrated to inhibit activation of the NFAT family of transcription factors (45)(46)(47), transcription factors that appear to mediate some of the pro-growth and pro-survival effects of vascular endothelial growth factor in endothelial cells (48,49).…”