MAP-1, a Novel Proapoptotic Protein Containing a BH3-like Motif That Associates with Bax through Its Bcl-2 Homology Domains

Abstract

A novel Bax-associating protein, named MAP-1 (Modulator of Apoptosis), has been identified in a yeast twohybrid screen. MAP-1 contains a BH3-like (BH: Bcl-2 homology) motif and mediates caspase-dependent apoptosis in mammalian cells when overexpressed. MAP-1 homodimerizes and associates with the proapoptotic Bax and the prosurvival Bcl-2 and Bcl-X L of the Bcl-2 family in vitro and in vivo in mammalian cells. Mutagenesis analyses revealed that the BH3-like domain in MAP-1 is not required for its association with Bcl-X L but is required for association with Bax and for mediating apoptosis. Interestingly, in contrast to other Bax-associating proteins such as Bcl-X L and Bid, which require the BH3 and BH1 domains of Bax, respectively, for binding, the binding of MAP-1 to Bax appears to require all three BH domains (BH1, BH2, and BH3) of Bax, because point mutation of the critical amino acid in any one of these domains is sufficient to abolish its binding to MAP-1. These data suggest that MAP-1 mediates apoptosis through a mechanism that involves binding to Bax.

Sequence-specific Dimerization of the Transmembrane Domain of the “BH3-only” Protein BNIP3 in Membranes and Detergent

“…BH3-only proteins appear to connect specific signaling pathways to the Bcl-2/Bax apoptosis checkpoint (15,16), but the nature of this regulation may be quite diverse, because some BH3-only proteins bind the anti-apoptotic Bcl-2 subfamily members (56,62), whereas others are capable of binding to either Bcl-2 or Bax (63,64). The BH3-only protein BNIP3 interacts with anti-apoptotic Bcl-2 subfamily members, including Bcl-x L , but neither the mammalian nor Caenorhabditis elegans orthologs of BNIP3 require a BH3 domain to bind to Bcl-x L (22,65).…”

Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria

“…MOAP-1 is proapoptotic in mammalian cells when overexpressed (10,11). Reduction of MOAP-1 levels by RNAi knockdown suppresses apoptosis triggered by multiple apoptotic stimuli (11).…”

“…MOAP-1 contains a BH3-like motif and is capable of triggering apoptosis in mammalian cells when overexpressed (10,11). Knocking down MOAP-1 by RNAi confers inhibition of apoptotic signaling triggered by multiple apoptotic stimuli and promotes anchorage-independent growth of tumor cells (11).…”

“…Modulator of apoptosis (MOAP-1), initially named MAP-1, was identified as a binding partner of Bax in a yeast two hybrid screen (10). MOAP-1 contains a BH3-like motif and is capable of triggering apoptosis in mammalian cells when overexpressed (10,11).…”

New molecular insights into peripheral T cell lymphomas

“…In particular, an analysis of ours (10) might explain the dissemination pattern of PTCL-NOSs, which involves frequent extranodal sites and bone marrow and spreads to peripheral blood, because it demonstrates the upregulation of the FN1, LAMB1, COL1A2, COL3A1, COL4A1, COL4A2, and COL12A1 genes, which promote local invasion and metastasis in different types of human cancers (33)(34)(35). In addition, our analysis revealed the deregulation of genes involved in apoptosis (e.g., MOAP1, ING3, GADD45A and GADD45B) (36)(37)(38)(39)(40)(41)(42) and chemo-resistance (e.g., CYR61 and NNMT) (33)(34)(35)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53), which may be responsible for the poor response to conventional chemotherapy.…”