Disease relevance of MNAT1

• p35 and p37 are Borrelia burgdorferi genes encoding 35 and 37 kDa proteins [1].
• We now report that the E1B19K protein from adenovirus and the p35 protein from baculovirus also rescue neurons [2].
• Hyperplasia of vascular smooth muscle cells (SMC) is a fundamental pathologic feature of luminal narrowing in vascular occlusive diseases, and nothing is yet known regarding the cell cycle phase specificity of the MAT1 gene in its involvement in SMC proliferation [3].
• In summary, these results indicate that the p32-p36 complex represents a family of structural proteins closely associated with the assembly of VZV nucleocapsids and the encapsidation of viral DNA [4].
• Varicella-zoster virus p32/p36 complex is present in both the viral capsid and the nuclear matrix of the infected cell [4].

High impact information on MNAT1

• A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death [5].
• In contrast, p35 delayed onset without slowing disease progression [6].
• Addition of the MAT1 subunit to recombinant bipartite CDK7-CycH switched its substrate preference to favour the pol II large subunit C-terminal domain (CTD) over CDK2 [7].
• We suggest that the MAT1 protein, previously shown to function as an assembly factor for CDK7-CycH, also acts to modulate CAK substrate specificity [7].
• Sequencing of MAT1 reveals a putative zinc binding motif (a C3HC4 RING finger) in the N-terminus; however, this domain is not required for ternary complex formation with CDK7-cyclin H [8].

Chemical compound and disease context of MNAT1

• Members of the baculovirus p35 gene family encode proteins that specifically inhibit caspases, cysteine proteases that are involved in apoptosis [9].

Biological context of MNAT1

• Protein labeling experiments indicate that the p62 and p36 subunits of TFIIH are in vitro substrates for mitotic phosphorylation [10].
• The physical interaction between MAT1 and MCM7 was confirmed in vivo in yeast cells and verified with in vitro protein binding assays [11].
• Viral proteins E1B19K and p35 protect sympathetic neurons from cell death induced by NGF deprivation [2].
• We demonstrate the ability of the p35 gene to inhibit oxidative stress-induced apoptosis [12].
• Transfection of cells with a recombinant plasmid containing the p35 gene under the transcriptional control of a stress promoter (Drosophila hsp70) was also able to rescue cells from oxidative stress-induced cell death, demonstrating the direct involvement of P35 [12].

Anatomical context of MNAT1

• E1B19K and p35 were also coinjected with Bcl-Xs which blocks Bcl-2 function in lymphoid cells [2].
• A role for the p36 MBPK in eosinophil cell death was supported by studies showing increased activation upon exposure to the proapoptotic Fas/CD95-activating antibody, CH-11, and attenuation in the presence of the survival-promoting cytokine, interleukin-5 [13].
• RNA antisense abrogation of MAT1 induces G1 phase arrest and triggers apoptosis in aortic smooth muscle cells [3].
• We now demonstrate that caspase-9 is activated at an early stage of apoptosis in epithelial cells and all its detectable, catalytically active large subunits (both the p35 and p37) are concentrated on cytokeratin fibrils [14].
• These results imply that although the final apoptotic events are blocked by p35, parts of the upstream apoptotic pathway that affect mitochondria are already activated by Apoptin [15].

Associations of MNAT1 with chemical compounds

• MAT1 contains a highly conserved C3HC4 motif at its NH2 terminus, a characteristic feature shared among RING finger proteins [16].
• We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo [17].
• Because HL60R cells that harbor a truncated ligand-dependent AF-2 domain of RARalpha do not demonstrate any changes in MAT1 levels or CAK phosphorylation of RARalpha following ATRA stimuli, these biochemical changes appear to be mediated directly through RARalpha [18].
• The switch to CAK hypophosphorylation of RARalpha is accompanied by decreased MAT1 expression and MAT1 fragmentation that occurs in the differentiating cells through the all-trans-retinoic acid (ATRA)-mediated proteasome degradation pathway [18].
• Although considerable information has emerged on the molecular properties of the p36 target protein its function as well as the possible implications of its tyrosine phosphorylation have remained elusive [19].

Physical interactions of MNAT1

• Here we report that in vitro reconstitution of an active CDK7-cyclin H complex requires stoichiometric amounts of a novel 36 kDa assembly factor termed MAT1 (ménage à trois 1) [8].
• MAT1-containing TFIIH was also shown to interact with POU domains of Oct-1 and Oct-2 [20].
• PGC-1 bound to both MAT1 and Cdk7 in coprecipitation assays [21].

Regulatory relationships of MNAT1

• Furthermore, spontaneous and Fas-induced activation of p36 MBPK was inhibited by catalase and the general caspase inhibitor, z-Asp-CH(2)-DCB, at concentrations that suppressed eosinophil apoptosis [13].
• CAK phosphorylation of PML/RARalpha is inhibited when MAT1 levels are reduced [22].

Other interactions of MNAT1

• Furthermore, we show that p36 and p53 can interact both in vitro and in vivo [23].
• We find that the p36/MAT1 subunit of CAK is required for transcriptional repression and the repression is independent of the promoter used [24].
• Using a yeast two-hybrid screen with the MTA1 C-terminal domain as bait, we identified MAT1 (ménage á trois 1) as an MTA1-binding protein [17].
• In addition, MAT1 interacts with the activation function 2 domain of ER and colocalizes with ER in activated cells [17].
• The kinase is composed of three subunits: CDK7, Cyclin H and MAT1 (ménage a trois) [25].

Analytical, diagnostic and therapeutic context of MNAT1

• In this animal model gene transfer of p35 prevented the rise in caspase 3 activity and DNA-histone formation [26].
• Adenoviral gene transfer of the caspase inhibitor p35 leads to a significant reduction of the myocardial infarct size after ischemia and reperfusion [27].
• PCR with primer pairs corresponding to the borders of the C. heterostrophus and the N. crassa HMG boxes generated an approximately 0.3-kb product from genomic DNAs of MAT-2 and mt a strains, respectively, but not from MAT-1 and mt A strains [28].
• Its immunoprecipitation from detergent-solubilized membrane extracts reveals two associated polypeptides with apparent molecular masses of 33 and 36 kDa (p33 and p36) that are absent in NSF-myc immunoprecipitates from cytosol [29].
• These findings suggest that p35 could be incorporated as part of a multi-pronged approach of immunoprotective strategies to provide protection from recurring autoimmunity for transplanted beta-cells, as well as in preventive gene therapy in type 1 diabetes. p35 may also be protective from beta-cell damage caused by hIAPP in type 2 diabetes [30].

References