Modulator of Apoptosis 1 (MOAP-1) Is a Tumor Suppressor Protein Linked to the RASSF1A Protein

Jennifer Law,Mohamed Salla,Alaa Zare,Yoke Wong,Le Luong,Natalia Volodko,Orysya Svystun,Kayla Flood,Jonathan Lim,Miranda Sung,Jason R.B Dyck,Chong Teik Tan,Yu-Chin Su,Victor C Yu,John Mackey,Shairaz Baksh

doi:10.1074/jbc.m115.648345

Abstract

Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein has yet to be determined. In this study, we present several lines of evidence from cancer databases, immunoblotting of cancer cells, proliferation, and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA down-regulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and up-regulation of genes involved in cancer regulatory pathways that include apoptosis (p53, Fas, and MST1), DNA damage control (poly(ADP)-ribose polymerase and ataxia telangiectasia mutated), those within the cell metabolism (IR-α, IR-β, and AMP-activated protein kinase), and a stabilizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer, and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor-dependent pathway and drive tumorigenesis.

Highlights

Differential expression analysis of Modulator of Apoptosis 1 (MOAP-1) was carried out in samples from normal versus malignant tissues with data subsequently compiled from microarray studies meeting the threshold foldchange Ն1.5 and p value Յ 0.05
The results obtained from this meta-analysis indicate that MOAP-1 expression is markedly reduced in multiple types of human cancers (Fig. 1A), especially in the brain, breast, blood, skin, and lung suggesting that loss of MOAP-1 is important for tumorigenesis to occur
Kaplan-Meier survival analysis demonstrated that patients with high expression of either MOAP-1 or Ras association domain family 1A (RASSF1A) experienced greater survival rates versus those with low expression of either gene (Fig. 1, B and C), thereby suggesting that both MOAP-1 and RASSF1A may behave as tumor suppressor proteins in the pathogenesis of neuroblastoma

Summary

Background

We can demonstrate that MOAP-1 may carry out its tumor suppressor function by the involvement in apoptosis [2, 8] and associations with tubulin isoforms to stabilize tubulin (this study). This will aid in sister chromatid separation in a similar manner to RASSF1A [11, 12]. We provide evidence for involvement in DNA damage control and cell metabolism that may influence control of tumor formation These studies illustrate important links to RASSF1A (a bona fide tumor suppressor protein) and suggest that MOAP-1 synergizes with RASSF1A to inhibit tumorigenesis

Materials and Methods

Results

D MOAP-1 Protein Expression in Breast Cancer Cells

Discussion