Gadd45-[alpha] and Gadd45-[gamma] utilize p38 and JNK signaling pathways to induce cell cycle G2/M arrest in Hep-G2 hepatoma cells

The Gadd45 family of proteins, which includes [alpha], [beta], and [gamma] isoforms, has recently been shown to play a role in the G2/M cell cycle checkpoint in response to DNA damage; however, the mechanisms by which Gadd45 proteins inhibit cell cycle control are not fully understood. Using immunohistochemical analysis, we found that protein expression of Gadd45[gamma], but not Gadd45[alpha], was down-regulated in hepatocellular carcinoma. We thus investigated possible mechanisms by which Gadd45[alpha] and Gadd45[gamma] might differentially induce G2/M arrest in the human hepatoma Hep-G2 cell line. Flow cytometric analysis revealed significant G2/M arrest in cells transfected with either Gadd45[alpha] or Gadd45[gamma]. Importantly, we found that expression of either Gadd45[alpha] or Gadd45[gamma] activated the P38 and JNK kinase pathways to induce G2/M arrest. Taken together, these findings suggest that the induction of G2/M arrest by Gadd45[alpha] or Gadd45[gamma] involves activation of two distinct signaling pathways in Hep-G2 hepatoma cell lines. [PUBLICATION ABSTRACT]