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: To directly validate the tumor suppressor function of MOAP-1 in vivo, xenograft tumor assays were performed in athymic nude mice lacking a functioning immune system (25). To carry out these assays, we selected cancer cell lines with reduced or absent MOAP-1 expression (DAOY medulloblastoma cells, SKOV3 and H1299) or with a detectable amount of MOAP-1 (HCT116 cells). Myc-MOAP-1 was transiently expressed in DAOY medulloblastoma cells, SKOV3 (stable expression, ovarian cancer) (Fig. 7, A and B), or H1299 (stable expression, lung cancer, Fig. 7, C and D) and transiently in HCT116 colon cancer cells (Fig. 8, A and B). Following subcutaneous injection of these cells into the left and right flanks of athymic mice, a significant difference in the growth of tumors containing overexpressed Myc-MOAP-1 emerged for all cell lines tested when compared with tumors containing a control vector. This suggested a role for MOAP-1 in growth suppression. Interestingly, the loss of the function of the BH3 domain of MOAP-1 (either as a deletion or mutation) resulted in the inability to suppress tumor formation to suggest a significant dependence of MOAP-1 on its pro-apoptotic function to carry out tumor suppression (Fig. 7, C and D). Complementary to our overexpressed cells, shRNA knockdown of MOAP-1 resulted in a significant increase in tumor formation following subcutaneous injection of HCT116 cells containing shRNA to MOAP-1 (Fig. 8C). Not surprisingly, tumor formation was additionally reduced in the presence of HA-RASSF1A (for DAOY and H1299 cells, Fig. 7, B and C) suggesting a requirement for the RASSF1A/MOAP-1 apoptotic pathway in inhibiting tumor formation in these cell lines.