Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells

Abstract

Parkin is known to be a tumor suppressor protein. It was reported that Parkin was mutated or its expression reduced in a variety of cancer cells and reintroduction of Parkin into cancer cells suppressed cancer cell growth. There are several reports proposed the mechanism of Parkin acting as a tumor suppressor, nevertheless, it still remains to be fully elucidated. Malignant tumors usually possesses resistance toward tumor necrosis factor-alpha (TNF-α). Previously, our laboratory determined that parkin expression restores susceptibility to TNF-α-induced death of HeLa cells, a human cervical cancer cell line resistant to TNF-α-induced cell death. However, tumor suppressors often act in a multiple mechanisms. In this study, I investigated the role of Parkin in growth of cancer cells. I found that Parkin expression inhibits cell division cycle 2 (CDC2) activity via phosphorylation of CDC2 at Tyr15, thereby inducing G2/M cell cycle arrest. This seems to be due to the Parkin induced phosphorylation of cell division cycle 25C (CDC25C) and increased Myt1 protein level both of which are associated with the CDC2 phosphorylation. Furthermore, Parkin expression resulted in the dephosphorylation of histone H3 which may hinder the chromatin condensation that is essential for cell division. These results suggest that Parkin acts as a tumor suppressor not only by inducing apoptotic cancer cell death but also by regulating cell cycle progression via novel molecular mechanism I proposed.