探討Myc/Max調控PML之機制

Abstract

The promyelocytic leukemia protein (PML) was identified in acute promyelocytic leukemia, in which chromosome translocation generates oncogenic PML-RARα fusion protein. The PML protein is essential for the assembly of PML-nuclear bodies (PML-NBs) and is a tumor suppressor. Through lentivirus-based shRNAs screening, previous study in our laboratory identified nine oncogenes and one tumor suppressor as putative regulators of PML-NBs. Using RNA interference and overexpression strategies to validate their effects on PML expression, we confirmed that Myc, Max, and Src are negative regulators of PML. We next investigated the mechanism underlying Myc/Max-induced PML downregulation. We observed that Myc/Max suppress PML mRNA expression and repress PML promoter activity. We further identified that a 0.2 kb PML promoter segment is responsible for Myc/Max binding and Myc/Max-mediated transcription repression. Besides transcriptional repression, we found that Myc/Max also accelerate PML protein turnover by increasing PML ubiquitiantion. Interestingly, this effect is not due to upregulation of previously identified PML E3 ligases RNF4 and KLHL20, but is likely mediated by a Cullin 4A/B-family of E3 ligase. In conclusion, our study identifies Myc/Max as PML negative regulators and indicates that Myc/Max regulate PML through both transcriptional and post-translational mechanisms.