Abstract
Membrane-bound CD40L (mCD40L) but not soluble CD40L (sCD40L) has been implicated in direct cell death induction and apoptosis in CD40-expressing carcinomas. In this study, we show that mCD40L but not sCD40L induces NORE1A/Rassf5 expression in an NFκB-dependant mechanism. NORE1A expression appeared to contribute to mCD40L-induced cell death and enhance cell transition from G1 to S phase of the cell cycle in a p21-dependent mechanism. The upregulation of p21 protein was attributed to NORE1A expression, since NORE1A inhibition resulted in p21 downregulation. p21 upregulation was concomitant with lower p53 expression in the cytoplasmic fraction with no detectable increase at the nuclear p53 level. Moreover, mCD40L-induced cell death mediated by NORE1A expression appeared to be independent of mCD40L-induced cell death mediated by sustained JNK activation since NORE1A inhibition did not affect JNK phosphorylation and vice versa. The presented data allow better understanding of the mechanism by which mCD40L induces cell death which could be exploited in the clinical development of CD40-targeted anti-cancer therapies.
Highlights
cyclin-dependent kinases (CDKs) inhibitors function through inhibition of the G1 CDK cyclin complexes.[4]
NORE1A protein expression results in a decrease in the number of cells in S phase of the cell cycle,[15] indicating that NORE1A might function as a tumour suppressor; here, we show for the first time that membrane-bound CD40L (mCD40L) but not soluble CD40L (sCD40L) induces the expression of NORE1A in an NFκB-dependant manner
The activation of CD40 receptor by sCD40L even at high concentration (1 μg/ml) failed to induce NORE1A expression in any of the examined CD40-positive carcinomas, indicating that NORE1A expression is restricted to activation of the CD40 receptor with mCD40L but not the soluble counterpart
Summary
CDK inhibitors function through inhibition of the G1 CDK cyclin complexes.[4]. the CDK inhibitor p21 has the ability to inhibit DNA synthesis by binding to and inhibiting proliferating cell nuclear antigen.[5,6,7] p21 protein expression is tightly regulated by the p53 tumour suppressor gene.[8]. NORE1A expression was found to contribute to mCD40Linduced cell death since inhibition of mCD40L-induced NORE1A expression resulted in reduced cell death by mCD40L. The role of CD40-induced NORE1A expression in cell cycle regulation was examined and found to be mediated by p21 upregulation
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