BMCC1, which is an interacting partner of BCL2, attenuates AKT activity, accompanied by apoptosis.

Y Tatsumi,Y Nakamura,T Yokochi,M S Islam,M Itami,A Nakagawara,R Takano

doi:10.1038/cddis.2014.568

Abstract

BNIP2 and Cdc42GAP homology (BCH) motif-containing molecule at the carboxyl-terminal region 1 (BMCC1) gene is highly expressed in patients with favorable neuroblastoma (NB). It encodes a 340-kDa protein with a conserved BCH scaffold domain that may regulate signaling networks and multiple cellular functions, including apoptosis. In this study, we determined the mechanism by which BMCC1 promotes apoptosis in human NB and non-NB cells, as BMCC1 is normally expressed in various organs, particularly in neuronal and epithelial tissues. We demonstrated in this report that BMCC1 was induced by DNA damage, one of the triggers of intrinsic apoptosis. Accordingly, we investigated whether BMCC1 expression impacts intracellular signals in the regulation of apoptosis via its C-terminal region containing BCH scaffold domain. BMCC1 decreased phosphorylation of survival signals on AKT and its upstream kinase PDK1. BMCC1 upregulation was correlated with the activation of forkhead box-O3a (FOXO3a) (a downstream inducer of apoptosis, which is suppressed by AKT) and induction of BCL2 inhibitor BIM, suggesting that BMCC1 negatively regulates phosphorylation pathway of AKT, resulted in apoptosis. In addition, we found that BNIP2 homology region of BMCC1 interacts with BCL2. Intrinsic apoptosis induced by DNA damage was enhanced by BMCC1 overexpression, and was diminished by knockdown of BMCC1. Taken together, we conclude that BMCC1 promotes apoptosis at multiple steps in AKT-mediated survival signal pathway. These steps include physical interaction with BCL2 and attenuation of AKT-dependent inhibition of FOXO3a functions, such as transcriptional induction of BIM and phosphorylation of ataxia telangiectasia-mutated (ATM) after DNA damage. We propose that downregulation of BMCC1 expression, which is frequently observed in unfavorable NB and epithelial-derived cancers, may facilitate tumor development by abrogating DNA damage repair and apoptosis.

Highlights

Sympathoadrenal cervical ganglions prepared from BMCC1 transgenic mice undergo accelerated apoptosis induced by withdrawing nerve growth factor (NGF), and BMCC1 is expressed in neuronal cells in which programmed cell death was induced by retinoic acid and NGF withdrawal.[16]
We demonstrated that BMCC1 induces apoptosis in human tumor cells, resulting in tumor suppression
BMCC1 binds to BCL2 through the BNIP2 homology region containing BH3 homology domain

Summary

Introduction

The molecular mechanism of spontaneous regression in NB remains unknown To better understand this mechanism, we investigated genes differentially expressed among clinical samples obtained from patients with the favorable and unfavorable NB subsets.[12,13] We identified several genes with unknown function, which were highly expressed in favorable NB, such as UNC5D14 and Src homology 2 domain containing F (Shf).[15]. Inhibition of BMCC1 expression resulted in a decrease in apoptosis induced by DNA damage This result is consistent with consequence of the inhibition of FOXO3a functions, such as BIM induction and increased ataxia telangiectasia-mutated (ATM) phosphorylation, which depends on phosphorylation of AKT

Methods

Results

Conclusion