Post-translational modification of cyclin A1 is associated with staurosporine and TNFalpha induced apoptosis in leukemic cells.
Publikation/Tidskrift/Serie: Molecular and cellular biochemistry
Understanding of molecular mechanisms underlying the effects of cell cycle proteins in response to the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to chemotherapeutic agents. Staurosporine and tumor necrosis factor alpha (TNFalpha) are the therapeutic agents that inhibit tumor cell growth by inducing cell death. Staurosporine induces apoptosis through the intrinsic pathway, while TNFalpha trigger the cell death via the extrinsic apoptotic pathway. We have previously demonstrated that the cell cycle regulatory protein, cyclin A1 played an important role in the development of acute myeloid leukemia (AML), and cyclin A1 expression correlated with disease characteristics and patient outcome in leukemia. However, it remains unknown how cyclin A1 expression is regulated in leukemic cells treated with the therapeutic agents. Here, we demonstrate that cyclin A1 protein is regulated by proteasome-mediated ubiquitination and degradation in untreated U-937 cells. Interestingly, ubiquitination- and proteasomal-mediated degradation of cyclin A1 is prevented in cells treated with staurosporine or TNFalpha. Induction of apoptosis in U-937 cells by staurosporine or TNFalpha resulted in an increase in cyclin A1 protein expression, which correlated well with cyclin A1 protein modification and the activation of caspase-3. Blocking caspases activity by Z-VAD-FMK had no effect on the increased cyclin A1 expression, suggesting that cyclin A1 might be regulated by caspase-3 independent pathways. We further propose that CDC25C may be associated with cyclin A1 protein modification in response to staurosporine or TNFalpha treatment. Our results suggest that cyclin A1 protein is stabilized via post-transcriptional modification in response to apoptosis induced by staurosporine or TNFalpha.
- Medicine and Health Sciences
- ISSN: 0300-8177