Casein kinase 1alpha interacts with retinoid X receptor and interferes with agonist-induced apoptosis.
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 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 1alpha (CK1alpha). CK1alpha associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an 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.
Zhao
Yi
Y
Retinoid Research, Department of Biology, Allergan Inc., Irvine, California 92612, USA. zhao_yi@allergan.com
Qin
Suofu
S
Atangan
Larissa I
LI
Molina
Yanira
Y
Okawa
Yumiko
Y
Arpawong
Hieu T
HT
Ghosn
Corine
C
Xiao
Jia-Hao
JH
Vuligonda
Vidyasagar
V
Brown
Geoffrey
G
Chandraratna
Roshantha A S
RA
D000818:Animals; D017209:Apoptosis; D047388:Casein Kinases; D002460:Cell Line; D002470:Cell Survival; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D008024:Ligands; D016399:Lymphoma, T-Cell / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D008024:Ligands; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D011494:Protein Kinases; D047388:Casein Kinases