Sanjay Kumar
Jackson state University, USA
Title: Trisenox disrupts MDM2-DAXX-HAUSP complex and degradation of MDM2 in acute promyelocytic leukemia cells.
Biography
Biography: Sanjay Kumar
Abstract
Trisenox (TX) alone or combination with all trans retinoic acid (ATRA) has been successfully used in the treatment of acute promyelocytic leukemia (APL) patients with highest survival rate. Clinical trials study of TX and their combination with ATRA was shown complete remission in both de novo and relapsed APL patients. However, the exact molecular mechanisms of its action through cell cycle arrest and apoptosis are poorly understood. We hypothesized that TX modulates cell cycle and apoptosis through activation of p53 and interaction of death domain-associated protein (DAXX), which disrupted the MDM2-DAXX-HAUSP interaction, MDM2 degradation and their self –ubiquitination. To test the hypothesis, we used western blotting, confocal imaging and other molecular techniques to identify new target of TX action in APL cells. We found that the expression levels of p53 and p21 increased significantly, whereas MDM2, DAXX and HAUSP decreased in a dose dependent. Our immunoprecipitation (IP) studies shown that they are well associated each other in cells and TX disrupted their association. After 21 days treatment of TX different doses (1.25, 2.5, 5.0 and 7.5 mg/kg body wt) in transgenic mice, we isolated liver tissue and bone marrow cells. We found, p53 was activated in a dose dependent TX treated mice. We conclude that TX disrupts MDM2-DAXX-HAUSP complex, release and degradation of MDM2 expression in APL cells. It leads to accumulation of p53, cell cycle arrest and apoptosis in APL cells. It is novel target for treatment of APL patients by TX and also designing of new drugs.
