Phosphorylation‐Dependent Regulation of The Promyelocytic Leukemia Protein (PML)

The promyelocytic leukemia protein (PML) is a tumor suppressor that has an important role in several cellular processes including apoptosis, viral infection, DNA damage repair, cell cycle regulation, and senescence. PML is an essential component of a sub‐nuclear structure called PML nuclear bodies (NBs). Our lab has previously demonstrated that the peptidyl‐prolyl cis‐trans isomerase Pin1 binds and targets PML for degradation in a phosphorylation‐dependent manner. To further elucidate the mechanisms underlying Pin1‐mediated PML degradation, we aim to identify factor(s) that promote PML phosphorylation. Here we show that treatment of U0126, an inhibitor of the ERK2 upstream kinases MEK1/2 leads to an increase in PML protein levels and an inhibition of the interaction between Pin1 and PML in MDA‐MB‐231 breast cancer cells. Furthermore, while U0126 up‐regulates exogenous wild‐type PML levels, it does not have an effect on the steady‐state levels of mutant PML that is defective in binding Pin1. In addition, the exogenous wild type PML protein expression levels were decreased by overexpression of ERK2, but the mutant PML levels remained unchanged. Moreover, knockdown of ERK2 by siRNA results in an increase in PML protein levels and an increase in the formation of PML NBs. Taken together, our results support a model in which Pin1 promotes PML degradation in an ERK2‐dependent manner.