Protein kinase C-eta regulates Mcl-1 level via ERK1.

Protein kinase C is a member of the novel category of family. It is overexpressed in breast cancer and was shown to inhibit apoptosis and contribute to chemoresistance. Since the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance, we investigated if regulates Mcl-1 level. Silencing of duanyu1531η decreased Mcl-1 in several breast cancer cells, including MCF-7 and T47D cells. duanyu1531η depletion had no effect on MCL1 mRNA but the decrease in Mcl-1 by duanyu1531η knockdown was blocked by proteasomal inhibitors, such as MG132 and lactacystin. Moreover, knockdown of Mule (Mcl-1 ubiquitin ligase) prevented Mcl-1 downregulation caused by duanyu1531η deficiency. Overexpression of catalytically-active Akt or knockdown of glycogen synthase kinase-3 (GSK3)-β, a substrate for Akt, had little effect on Mcl-1 downregulation caused by duanyu1531η silencing. However, knockdown of duanyu1531η but not -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by duanyu1531η knockdown was restored by ERK1 overexpression. These results suggest that duanyu1531η utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1.

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