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Gene Review

MNAT1  -  MNAT CDK-activating kinase assembly factor 1

Homo sapiens

Synonyms: CAP35, CDK-activating kinase assembly factor MAT1, CDK7/cyclin-H assembly factor, Cyclin-G1-interacting protein, MAT1, ...
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Disease relevance of MNAT1


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


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


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].


  1. Borrelia burgdorferi P35 and P37 proteins, expressed in vivo, elicit protective immunity. Fikrig, E., Barthold, S.W., Sun, W., Feng, W., Telford, S.R., Flavell, R.A. Immunity (1997) [Pubmed]
  2. Viral proteins E1B19K and p35 protect sympathetic neurons from cell death induced by NGF deprivation. Martinou, I., Fernandez, P.A., Missotten, M., White, E., Allet, B., Sadoul, R., Martinou, J.C. J. Cell Biol. (1995) [Pubmed]
  3. RNA antisense abrogation of MAT1 induces G1 phase arrest and triggers apoptosis in aortic smooth muscle cells. Wu, L., Chen, P., Hwang, J.J., Barsky, L.W., Weinberg, K.I., Jong, A., Starnes, V.A. J. Biol. Chem. (1999) [Pubmed]
  4. Varicella-zoster virus p32/p36 complex is present in both the viral capsid and the nuclear matrix of the infected cell. Friedrichs, W.E., Grose, C. J. Virol. (1986) [Pubmed]
  5. A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death. Sahlgren, C.M., Pallari, H.M., He, T., Chou, Y.H., Goldman, R.D., Eriksson, J.E. EMBO J. (2006) [Pubmed]
  6. The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. Inoue, H., Tsukita, K., Iwasato, T., Suzuki, Y., Tomioka, M., Tateno, M., Nagao, M., Kawata, A., Saido, T.C., Miura, M., Misawa, H., Itohara, S., Takahashi, R. EMBO J. (2003) [Pubmed]
  7. Regulation of CDK7 substrate specificity by MAT1 and TFIIH. Yankulov, K.Y., Bentley, D.L. EMBO J. (1997) [Pubmed]
  8. In vitro assembly of a functional human CDK7-cyclin H complex requires MAT1, a novel 36 kDa RING finger protein. Tassan, J.P., Jaquenoud, M., Fry, A.M., Frutiger, S., Hughes, G.J., Nigg, E.A. EMBO J. (1995) [Pubmed]
  9. Identification and functional characterization of AMVp33, a novel homolog of the baculovirus caspase inhibitor p35 found in Amsacta moorei entomopoxvirus. Means, J.C., Penabaz, T., Clem, R.J. Virology (2007) [Pubmed]
  10. Repression of TFIIH transcriptional activity and TFIIH-associated cdk7 kinase activity at mitosis. Long, J.J., Leresche, A., Kriwacki, R.W., Gottesfeld, J.M. Mol. Cell. Biol. (1998) [Pubmed]
  11. The MAT1 cyclin-dependent kinase-activating kinase (CAK) assembly/targeting factor interacts physically with the MCM7 DNA licensing factor. Wang, Y., Xu, F., Hall, F.L. FEBS Lett. (2000) [Pubmed]
  12. The baculovirus antiapoptotic p35 gene also functions via an oxidant-dependent pathway. Sah, N.K., Taneja, T.K., Pathak, N., Begum, R., Athar, M., Hasnain, S.E. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  13. Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis. De Souza, P.M., Kankaanranta, H., Michael, A., Barnes, P.J., Giembycz, M.A., Lindsay, M.A. Blood (2002) [Pubmed]
  14. Intermediate filaments control the intracellular distribution of caspases during apoptosis. Dinsdale, D., Lee, J.C., Dewson, G., Cohen, G.M., Peter, M.E. Am. J. Pathol. (2004) [Pubmed]
  15. The chicken anemia virus-derived protein apoptin requires activation of caspases for induction of apoptosis in human tumor cells. Danen-van Oorschot, A.A., van Der Eb, A.J., Noteborn, M.H. J. Virol. (2000) [Pubmed]
  16. Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor. Yee, A., Nichols, M.A., Wu, L., Hall, F.L., Kobayashi, R., Xiong, Y. Cancer Res. (1995) [Pubmed]
  17. MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions. Talukder, A.H., Mishra, S.K., Mandal, M., Balasenthil, S., Mehta, S., Sahin, A.A., Barnes, C.J., Kumar, R. J. Biol. Chem. (2003) [Pubmed]
  18. Retinoid-induced G1 arrest and differentiation activation are associated with a switch to cyclin-dependent kinase-activating kinase hypophosphorylation of retinoic acid receptor alpha. Wang, J., Barsky, L.W., Shum, C.H., Jong, A., Weinberg, K.I., Collins, S.J., Triche, T.J., Wu, L. J. Biol. Chem. (2002) [Pubmed]
  19. Repeating sequence homologies in the p36 target protein of retroviral protein kinases and lipocortin, the p37 inhibitor of phospholipase A2. Weber, K., Johnsson, N. FEBS Lett. (1986) [Pubmed]
  20. The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors. Inamoto, S., Segil, N., Pan, Z.Q., Kimura, M., Roeder, R.G. J. Biol. Chem. (1997) [Pubmed]
  21. Ménage-à-Trois 1 Is Critical for the Transcriptional Function of PPARgamma Coactivator 1. Sano, M., Izumi, Y., Helenius, K., Asakura, M., Rossi, D.J., Xie, M., Taffet, G., Hu, L., Pautler, R.G., Wilson, C.R., Boudina, S., Abel, E.D., Taegtmeyer, H., Scaglia, F., Graham, B.H., Kralli, A., Shimizu, N., Tanaka, H., Mäkelä, T.P., Schneider, M.D. Cell Metab. (2007) [Pubmed]
  22. Retinoic acid induces leukemia cell G1 arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RARalpha. Wang, J.G., Barsky, L.W., Davicioni, E., Weinberg, K.I., Triche, T.J., Zhang, X.K., Wu, L. FASEB J. (2006) [Pubmed]
  23. p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner. Ko, L.J., Shieh, S.Y., Chen, X., Jayaraman, L., Tamai, K., Taya, Y., Prives, C., Pan, Z.Q. Mol. Cell. Biol. (1997) [Pubmed]
  24. Inhibition of transcription by the trimeric cyclin-dependent kinase 7 complex. Bochar, D.A., Pan, Z.Q., Knights, R., Fisher, R.P., Shilatifard, A., Shiekhattar, R. J. Biol. Chem. (1999) [Pubmed]
  25. CAK-Cyclin-dependent Activating Kinase: a key kinase in cell cycle control and a target for drugs? Lolli, G., Johnson, L.N. Cell Cycle (2005) [Pubmed]
  26. Blocking caspase-activated apoptosis improves contractility in failing myocardium. Laugwitz, K.L., Moretti, A., Weig, H.J., Gillitzer, A., Pinkernell, K., Ott, T., Pragst, I., Städele, C., Seyfarth, M., Schömig, A., Ungerer, M. Hum. Gene Ther. (2001) [Pubmed]
  27. Gene transfer of the pancaspase inhibitor P35 reduces myocardial infarct size and improves cardiac function. Bott-Flügel, L., Weig, H.J., Knödler, M., Städele, C., Moretti, A., Laugwitz, K.L., Seyfarth, M. J. Mol. Med. (2005) [Pubmed]
  28. Efficient cloning of ascomycete mating type genes by PCR amplification of the conserved MAT HMG Box. Arie, T., Christiansen, S.K., Yoder, O.C., Turgeon, B.G. Fungal Genet. Biol. (1996) [Pubmed]
  29. Functional and molecular identification of novel members of the ubiquitous membrane fusion proteins alpha- and gamma-SNAP (soluble N-ethylmaleimide-sensitive factor-attachment proteins) families in Dictyostelium discoideum. Weidenhaupt, M., Bruckert, F., Louwagie, M., Garin, J., Satre, M. Eur. J. Biochem. (2000) [Pubmed]
  30. Baculovirus p35 increases pancreatic beta-cell resistance to apoptosis. Hollander, K., Bar-Chen, M., Efrat, S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
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