Abstract
Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in both the intrinsic and extrinsic modes of cell death or apoptosis. MOAP-1 is part of the Ras association domain family 1A (RASSF1A)/MOAP-1 pro-apoptotic extrinsic signaling pathway that regulates apoptosis by utilizing death receptors such as tumor necrosis factor α (TNFα) or TNF-related apoptosis-inducing ligand (TRAIL) to inhibit abnormal growth. RASSF1A is a bona fide tumor suppressor gene that is epigenetically silenced by promoter-specific methylation in numerous human cancers. MOAP-1 is a downstream effector of RASSF1A that promotes Bax activation and cell death and is highly regulated during apoptosis. We speculate that MOAP-1 and RASSF1A are important elements of an “apoptotic checkpoint” that directly influences the outcome of cell death. The failure to regulate this pro-apoptotic pathway may result in the appearance of cancer and possibly other disorders. Although loss of RASSF1A expression is frequently observed in human cancers, it is currently unknown if MOAP-1 expression may also be affected during carcinogenesis to result in uncontrolled malignant growth. In this article, we will summarize what is known about the biological role(s) of MOAP-1 and how it functions as a downstream effector to RASSF1A.
Highlights
Cancer is a disease of uncontrolled cell proliferation and is the third leading causing of death worldwide following cardiovascular and infectious diseases [2]
In response to death receptor signaling involving tumor necrosis factor α (TNFα) or TNF-related apoptosisinducing ligand (TRAIL), Ras association domain family 1A (RASSF1A) can associate with Modulator of apoptosis 1 (MOAP-1) in order to promote Bax conformational change, translocation and integration into the mitochondrial membrane to perturb mitochondrial permeability [5, 6]
MOAP-1-induced Bax conformational change enables Bax to translocate from the cytosol to the mitochondria where it can insert into the mitochondrial membrane and promote the release of cytochrome c as well as other apoptosisinducing factors, resulting in cell death
Summary
Cancer is a disease of uncontrolled cell proliferation and is the third leading causing of death worldwide following cardiovascular and infectious diseases [2]. The abnormal proliferation of cells during cancer development results from a multistep process involving the deregulation of genes that promote cell growth (oncogenes) and those that normally function to restrain growth (tumor suppressors). Approximately 90% of the genes that are associated with cancer development have been identified as being tumor suppressors [3]. Many of these growth inhibitory genes encode proteins that are involved in cell death. RASSF1A has multiple biological functions including the regulation of Bax-mediated cell death [4,5,6]. We will discuss how MOAP-1 is regulated and how it serves as a pivotal RASSF1A effector protein to regulate cell death
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