Inhibition of Ck2 Activity by Tgf–β1 Promotes IκB–α Protein Stabilization and Apoptosis of Immortalized Hepatocytes

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Abstract
Nuclear factor κB (NF–κB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor κB (IκB)–α protein following treatment of hepatocytes with transforming growth factor (TGF)–β1 promoted NF–κB repression, which then permitted induction of AP–1/SMAD–mediated liver cell death. Because basal IκB–α protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF–κB levels following treatment with TGF–β1. We show that both messenger RNA (mRNA) and protein levels of the CK2α catalytic subunit are down–regulated following TGF–β1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IκB protein, which is followed by the shutoff of constitutive NF–κB activity and induction of apoptosis. Ectopic expression of CK2α inhibits TGF–β1–induced apoptosis through sustained activation of NF–κB. Conversely, expression of a kinase–dead mutant of CK2α potentiates TGF–β1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF–β1 transgenic mice and human HCC cell lines display enhanced CK2 IκB kinase activity that contributes in part to an elevated NF–κB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF–β1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up–regulation of CK2 activity in transformed cells may contribute to the promotion of TGF–β1–induced liver carcinogenesis.