Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.
Bottom Line: 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.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.
Affiliation: From the Departments of Biochemistry and.Show MeSH
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Mentions: The role for MOAP-1 in cell death is well documented. MOAP-1 is known to partner with TNF-R1, RASSF1A, and Bax to promote apoptosis (1, 2) and partner with TRIM39 for protein stabilization (5). Although cell death and microtubule stability are important aspects of MOAP-1 biology, other possible mechanisms may exist to explain how MOAP-1 inhibits cell proliferation and tumor formation. To gain insight into these other mechanisms of tumor suppression, gene expression profiling was performed on MOAP-1-overexpressing xenograft tumors in nude mice. All experiments were carried out by transient transfections in HCT116 cells as described previously (11). Using this method, we were able to obtain >60% expression by day 2 that is sustained until day 10 after transfection in tissue culture (11). Because most of the tumor growth initiates between 7 and 14 days (as seen in Fig. 8, B and C), we postulate that >60% of the HCT116 cells expressing Myc-MOAP-1 will be sufficient to direct a growth path toward tumor suppression. RNA was extracted from resulting tumors and subjected to GWAS using the Agilent platform. GWAS revealed a total of 1434 differentially expressed genes by overexpression of MOAP-1 or, most likely, as a consequence of the biological ability of MOAP-1 to induce cell death and other physiological processes (Fig. 10A). Using the “core analysis” function in Ingenuity Pathway Analysis (Ingenuity Systems) (30), we were able to interpret gene expression changes in the context of biological functions and signaling pathways. Table 2 and Fig. 10B display several biological functions and signaling pathways identified as being most significant to the dataset of vector versus wild type MOAP-1 based on Fisher's exact test. Table 3 represents a selection of differentially expressed genes whose expression is modulated as a consequence of MOAP-1 overexpression and enhanced pro-apoptotic function, some of which encode potential growth-regulatory or tumor-suppressor functions. Cell death (805 molecules), cell growth and proliferation (625 molecules), and gene expression (545 molecules) were among the top biological functions associated with the dysregulated molecules (Fig. 10B).