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Gene Review

HINT1  -  histidine triad nucleotide binding protein 1

Homo sapiens

Synonyms: Adenosine 5'-monophosphoramidase, HINT, Histidine triad nucleotide-binding protein 1, NMAN, PKCI-1, ...
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Disease relevance of HINT1


Psychiatry related information on HINT1


High impact information on HINT1

  • Therefore, the paper by Lee et al. in this issue of Immunity that ascribes a role for the histidine triad protein HINT (also designated HINT1) in regulating the activity of the microphthalmia transcription factor (MITF) is of great interest [7].
  • Adhesion was affected by a qualitative change in LFA-1 molecules and was reversed by the protein kinase C inhibitor sphingosine [8].
  • We show that secretion of vimentin, which is phosphorylated at serine and threonine residues, is enhanced by the phosphatase inhibitor okadaic acid and blocked by the specific protein kinase C inhibitor GO6983 [9].
  • This stimulated release was shown to be (a) concentration- and time-dependent, (b) partially blocked by the protein synthesis inhibitor cycloheximide, and (c) significantly inhibited by the protein kinase C inhibitor Ro-31,8220 [10].
  • Upregulation by the B1-agonist was blocked by a specific protein kinase C inhibitor [11].

Chemical compound and disease context of HINT1


Biological context of HINT1


Anatomical context of HINT1

  • Northern blot analysis indicated that a 0.7-kb PKCI mRNA was expressed in several tissues obtained from adult mice and also in a variety of rodent and human cell lines [18].
  • Microscopy of immunostained cells indicated that the PKCI protein was present mainly in the nucleus of both normal and tumor-derived epithelial cell lines [18].
  • Indirect immunofluorescence shows that hPKCI-1 localizes to cytoskeletal structures in the cytoplasm of a human fibroblast cell line and is largely excluded from the nucleus [20].
  • Effect of the protein kinase C inhibitor staurosporine on chemosensitivity to daunorubicin of normal and leukemic fresh myeloid cells [22].
  • Contrasting actions of staurosporine, a protein kinase C inhibitor, on human neutrophils and primary mouse epidermal cells [23].

Associations of HINT1 with chemical compounds


Enzymatic interactions of HINT1


Regulatory relationships of HINT1


Other interactions of HINT1


Analytical, diagnostic and therapeutic context of HINT1

  • Western blot analyses, using a polyclonal antibody prepared against hPKCI, indicated that this protein is expressed at relatively high levels in several murine tissues and in a variety of human cell lines prepared from normal tissues or tumors [18].
  • The three-dimensional structure of protein kinase C interacting protein 1 (PKCI-1) has been solved to high resolution by x-ray crystallography using single isomorphous replacement with anomalous scattering [1].
  • Electron microscopy shows that a protein kinase C inhibitor does not impair binding of HIV to CD4+ cells, but causes an apparent accumulation of virus particles at the cell surface, at the same time inhibiting viral infectivity [39].
  • No prevention of ischemic preconditioning by the protein kinase C inhibitor staurosporine in swine [40].
  • This interaction was initially observed in a yeast two-hybrid study and subsequently verified by co-immunoprecipitation and subcellular localization studies, where overexpression of Cdk7 leads to partial relocalization of Hint to the nucleus [41].


  1. Three-dimensional structure of human protein kinase C interacting protein 1, a member of the HIT family of proteins. Lima, C.D., Klein, M.G., Weinstein, I.B., Hendrickson, W.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. Induction of endonuclease G-mediated apopotosis in human oral squamous cell carcinoma cells by protein kinase C inhibitor safingol. Hamada, M., Sumi, T., Iwai, S., Nakazawa, M., Yura, Y. Apoptosis (2006) [Pubmed]
  3. Modulation of apoptosis by mitochondrial uncouplers: apoptosis-delaying features despite intrinsic cytotoxicity. Stoetzer, O.J., Pogrebniak, A., Pelka-Fleischer, R., Hasmann, M., Hiddemann, W., Nuessler, V. Biochem. Pharmacol. (2002) [Pubmed]
  4. HIT family genes: FHIT but not PKCI-1/HINT produces altered transcripts in colorectal cancer. Elnatan, J., Murphy, D., Goh, H.S., Smith, D.R. Br. J. Cancer (1999) [Pubmed]
  5. Deletion of histidine triad nucleotide-binding protein 1/PKC-interacting protein in mice enhances cell growth and carcinogenesis. Su, T., Suzui, M., Wang, L., Lin, C.S., Xing, W.Q., Weinstein, I.B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  6. Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Brenner, C. Biochemistry (2002) [Pubmed]
  7. Mast cells provide a "HINT" to the function of an exotic nucleotide. Weinstein, I.B., Li, H. Immunity (2004) [Pubmed]
  8. Engagement of major histocompatibility complex class II molecules induces sustained, lymphocyte function-associated molecule 1-dependent cell adhesion. Mourad, W., Geha, R.S., Chatila, T. J. Exp. Med. (1990) [Pubmed]
  9. Vimentin is secreted by activated macrophages. Mor-Vaknin, N., Punturieri, A., Sitwala, K., Markovitz, D.M. Nat. Cell Biol. (2003) [Pubmed]
  10. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. Rossi, A.G., Haslett, C., Hirani, N., Greening, A.P., Rahman, I., Metz, C.N., Bucala, R., Donnelly, S.C. J. Clin. Invest. (1998) [Pubmed]
  11. The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts. Schanstra, J.P., Bataillé, E., Marin Castaño, M.E., Barascud, Y., Hirtz, C., Pesquero, J.B., Pecher, C., Gauthier, F., Girolami, J.P., Bascands, J.L. J. Clin. Invest. (1998) [Pubmed]
  12. Mitogenic activity of dermatofibrosarcoma protuberans is mediated via an extracellular signal related kinase dependent pathway. Ihn, H., Tamaki, K. J. Invest. Dermatol. (2002) [Pubmed]
  13. Phorbol ester reduces constitutive nuclear NF kappa B and inhibits HIV-1 production in mature human monocytic cells. Mufson, R.A., Myers, C., Turpin, J.A., Meltzer, M. J. Leukoc. Biol. (1992) [Pubmed]
  14. CD28:B7 interactions promote T cell adhesion. Turcovski-Corrales, S.M., Fenton, R.G., Peltz, G., Taub, D.D. Eur. J. Immunol. (1995) [Pubmed]
  15. The protein kinase C inhibitor, H-7, induces acute lung injury in guinea pigs. Tanigaki, T., Suzuki, Y., Heimer, D., Wang, W., Sussman, H.H., Ross, W.G., Murphy, G.A., Ikeda, H., Raffin, T.A. Crit. Care Med. (1994) [Pubmed]
  16. 17beta-estradiol antagonizes the down-regulation of endothelial nitric-oxide synthase and GTP cyclohydrolase I by high glucose: relevance to postmenopausal diabetic cardiovascular disease. Miyazaki-Akita, A., Hayashi, T., Ding, Q.F., Shiraishi, H., Nomura, T., Hattori, Y., Iguchi, A. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  17. Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal cortex are decreased in schizophrenia. Vawter, M.P., Shannon Weickert, C., Ferran, E., Matsumoto, M., Overman, K., Hyde, T.M., Weinberger, D.R., Bunney, W.E., Kleinman, J.E. Neurochem. Res. (2004) [Pubmed]
  18. Characterization of PKCI and comparative studies with FHIT, related members of the HIT protein family. Klein, M.G., Yao, Y., Slosberg, E.D., Lima, C.D., Doki, Y., Weinstein, I.B. Exp. Cell Res. (1998) [Pubmed]
  19. The product of the ataxia-telangiectasia group D complementing gene, ATDC, interacts with a protein kinase C substrate and inhibitor. Brzoska, P.M., Chen, H., Zhu, Y., Levin, N.A., Disatnik, M.H., Mochly-Rosen, D., Murnane, J.P., Christman, M.F. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  20. Cloning, mapping, and in vivo localization of a human member of the PKCI-1 protein family (PRKCNH1). Brzoska, P.M., Chen, H., Levin, N.A., Kuo, W.L., Collins, C., Fu, K.K., Gray, J.W., Christman, M.F. Genomics (1996) [Pubmed]
  21. Aberrant gene expression in human non small cell lung carcinoma cells exposed to demethylating agent 5-aza-2'-deoxycytidine. Yuan, B.Z., Jefferson, A.M., Popescu, N.C., Reynolds, S.H. Neoplasia (2004) [Pubmed]
  22. Effect of the protein kinase C inhibitor staurosporine on chemosensitivity to daunorubicin of normal and leukemic fresh myeloid cells. Laredo, J., Huynh, A., Muller, C., Jaffrézou, J.P., Bailly, J.D., Cassar, G., Laurent, G., Demur, C. Blood (1994) [Pubmed]
  23. Contrasting actions of staurosporine, a protein kinase C inhibitor, on human neutrophils and primary mouse epidermal cells. Sako, T., Tauber, A.I., Jeng, A.Y., Yuspa, S.H., Blumberg, P.M. Cancer Res. (1988) [Pubmed]
  24. The histidine triad superfamily of nucleotide-binding proteins. Brenner, C., Bieganowski, P., Pace, H.C., Huebner, K. J. Cell. Physiol. (1999) [Pubmed]
  25. Vacuole formation and cytokeratin rearrangement of hepatoma cells induced by teleocidin are not associated with down-regulation of protein kinase C. Kaneko, Y., Tsukamoto, A., Kurokawa, K. Cancer Res. (1991) [Pubmed]
  26. Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3. Bieganowski, P., Garrison, P.N., Hodawadekar, S.C., Faye, G., Barnes, L.D., Brenner, C. J. Biol. Chem. (2002) [Pubmed]
  27. Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway. Ino, K., Uehara, C., Kikkawa, F., Kajiyama, H., Shibata, K., Suzuki, T., Khin, E.E., Ito, M., Takeuchi, M., Itakura, A., Mizutani, S. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  28. Effects of sphingosine on phorbol ester-mediated changes in astrocyte morphology and protein phosphorylation. Harrison, B.C., Staskavage, D.L., Mobley, P.L. J. Neurosci. Res. (1991) [Pubmed]
  29. Aprataxin forms a discrete branch in the HIT (histidine triad) superfamily of proteins with both DNA/RNA binding and nucleotide hydrolase activities. Kijas, A.W., Harris, J.L., Harris, J.M., Lavin, M.F. J. Biol. Chem. (2006) [Pubmed]
  30. Apoptosis mediated by activation of the G protein-coupled receptor for parathyroid hormone (PTH)/PTH-related protein (PTHrP). Turner, P.R., Mefford, S., Christakos, S., Nissenson, R.A. Mol. Endocrinol. (2000) [Pubmed]
  31. Calcitriol and its synthetic analogue MC 903 inhibit the interleukin-2-induced migration of human lymphocytes. Fraher, L.J., Caveney, A.N., McFadden, R.G. Am. J. Respir. Cell Mol. Biol. (1995) [Pubmed]
  32. beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Giri, R., Shen, Y., Stins, M., Du Yan, S., Schmidt, A.M., Stern, D., Kim, K.S., Zlokovic, B., Kalra, V.K. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  33. Thyrotropin-releasing hormone-stimulated inositol trisphosphate formation is liable to thyrotropin-releasing hormone-induced desensitization by a calcium-dependent mechanism. Torjesen, P.A., Bjøro, T., Ostberg, B.C., Haug, E. Mol. Cell. Endocrinol. (1988) [Pubmed]
  34. Erythropoietin and interleukin-3 induce distinct events in erythropoietin receptor-expressing BA/F3 cells. Krosl, J., Damen, J.E., Krystal, G., Humphries, R.K. Blood (1995) [Pubmed]
  35. MAD analysis of FHIT, a putative human tumor suppressor from the HIT protein family. Lima, C.D., D'Amico, K.L., Naday, I., Rosenbaum, G., Westbrook, E.M., Hendrickson, W.A. Structure (1997) [Pubmed]
  36. Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca2+-sensitive PKC-dependent tyrosine kinase pathway. Hou, M., Pantev, E., Möller, S., Erlinge, D., Edvinsson, L. Acta Physiol. Scand. (2000) [Pubmed]
  37. Cultured human liver fat-storing cells produce monocyte chemotactic protein-1. Regulation by proinflammatory cytokines. Marra, F., Valente, A.J., Pinzani, M., Abboud, H.E. J. Clin. Invest. (1993) [Pubmed]
  38. Parathyroid hormone-related protein (107-139) stimulates interleukin-6 expression in human osteoblastic cells. De Miguel, F., Martinez-Fernandez, P., Guillen, C., Valin, A., Rodrigo, A., Martinez, M.E., Esbrit, P. J. Am. Soc. Nephrol. (1999) [Pubmed]
  39. Human immunodeficiency virus induces phosphorylation of its cell surface receptor. Fields, A.P., Bednarik, D.P., Hess, A., May, W.S. Nature (1988) [Pubmed]
  40. No prevention of ischemic preconditioning by the protein kinase C inhibitor staurosporine in swine. Vahlhaus, C., Schulz, R., Post, H., Onallah, R., Heusch, G. Circ. Res. (1996) [Pubmed]
  41. Interactions of Cdk7 and Kin28 with Hint/PKCI-1 and Hnt1 histidine triad proteins. Korsisaari, N., Mäkelä, T.P. J. Biol. Chem. (2000) [Pubmed]
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