MECHANISM OF NF-κB-REGULATED BALANCE OF ANTI-APOPTOTIC AND PRO-APOPTOTIC ACTIVITY BY CONTROLLING TRANSCRIPTION AND CLEAVAGE OF MCL-1

Abstract

Both pro- and anti-apoptotic activities of NF-κB transcription factor have been observed. The extensive studies have shown that NF-κB directly regulates the expression of anti-apoptotic genes of the Bcl-2 family, such as Bcl-2, Bcl-xL and Blf1/A1, and inhibit apoptosis. However, less is known about the mechanism by which NF-κB induces apoptosis. Our recent finding identified that Mcl-1 is a direct transcriptional target of NF-κB. NF-κB-regulated expression of Mcl-1 promotes proliferation and cell survival in pancreatic cancer cells. Surprisingly, during serum withdrawal-induced apoptosis in pancreatic cancer cells, we found that degradation and cleavage of Mcl-1 are completely dependent on NF-κB activity. The pancreatic cancer cells, which express a phosphorylation defective IκBα (IκBαM) for inhibiting the constitutive NF-κB activity, are resistant to serum withdrawal-induced apoptosis and Mcl-1 degradation. To further determine how Mcl-1 was degraded or cleaved, we treat pancreatic cancer cells with PS-341 or caspase inhibitors. We found that caspase-3 directly cleaves the Mcl-1 protein and TNF-α and IL-1α stimulation not only increases the expression of Mcl-1, but also increases the Mcl-1 cleavage. Collectively, our findings suggest that NF-κB plays the important roles in balancing the activities of both anti-apoptosis and pro-apoptosis by controlling transcription and cleavage of Mcl-1.