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Gene Review

Tcf12  -  transcription factor 12

Mus musculus

Synonyms: A130037E08Rik, ALF1, Alf1, Class A helix-loop-helix transcription factor ME1, DNA-binding protein HTF4, ...
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Disease relevance of Tcf12

  • Here we show that ALF1, a member of bHLH protein family of transcription factors, in vitro binds with differing affinities to distinct E-box sequences found in the U3 regulatory regions of Friend, Moloney, SL3-3, and Akv murine leukemia viruses (MLVs) as well as Friend spleen focus-forming virus (SFFV) [1].
  • The growth of the Moloney-virus-induced lymphoma YAC was examined in its strain of origin, A, as well as in 6 AF1 hybrids, ALF1, AB6F1, ACBF1, AABYF1, AACAF1 and AASWF1. "Hybrid resistance", i.e., lower frequency of incidence of tumor takes compared to simultaneous A controls, was observed in all of the tested hybrids [2].

Psychiatry related information on Tcf12


High impact information on Tcf12

  • The REB alpha sequence contains a region characterized by a leucine heptad repeat that is situated amino-terminal of the carboxy-terminally located bHLH domain [4].
  • It is proposed that this tissue-specific pattern of REB RNA splicing is involved in the determination of corresponding tissue-specific combinations of heterodimeric complexes of ubiquitous and tissue-restricted bHLH proteins [4].
  • Mi-2beta associates with the CD4 enhancer as well as the E box binding protein HEB and the histone acetyltransferase (HAT) p300, enabling their recruitment to the CD4 enhancer and causing histone H3-hyperacetylation to this regulatory region [5].
  • E2A and HEB are basic helix-loop-helix transcription factors essential for T cell development [6].
  • E2A, HEB, E2-2, and daughterless are basic helix-loop-helix (bHLH) proteins that play key roles in multiple developmental pathways [7].

Biological context of Tcf12


Anatomical context of Tcf12

  • During neurulation, Tcf12 transcripts are evident at high levels in the proliferating neuroepithelium of the neural folds and the cephalic mesenchyme [8].
  • We found that Tcf12 transcripts are detected in the embryonic ectoderm prior to neural induction during gastrulation [8].
  • Thus, the timing and location of Tcf12 expression combined with this severe neurulation defect support our hypothesis that the Tcf12 gene may be involved in the control of proliferating neural stem cells and progenitor cells and that it may be critical to sustain their undifferentiated state during embryonic and adult neurogenesis [8].
  • In the developing cortex and spinal cord, Tcf12 expression is restricted to the proliferative ventricular zones, indicating that Tcf12 expression is down regulated when these neuronal cells undergo their final differentiation [8].
  • Breeding tests among mice carrying different mutations revealed that E2-2 and HEB interact with E2A in many developmental processes including generation of B cells [11].

Associations of Tcf12 with chemical compounds

  • Interplay of the E box, the cyclic AMP response element, and HTF4/HEB in transcriptional regulation of the neurospecific, neurotrophin-inducible vgf gene [12].
  • PAC-1 transcription induced by phorbol myristate acetate stimulation and the expression of the v-ras or v-raf oncogene is mediated via the E-box motif and an AP-2-related site and coincides with increased binding activity of the constitutive 53-kDa E-box-binding protein and induced binding of AP-2 [13].
  • The deduced amino-acid sequence of the ME1 cDNA revealed that it consists of 149 amino acid residues, which contain a signal peptide characteristic of secretory proteins, six cysteine residues and a proline-rich region conserved in the orthologous proteins [14].
  • The DX16 mAb recognizes class I allotypes which possess alanine at position 71 of the alpha 1 helix, and therefore has a specificity resembling that of the ME1 mAb but with broader specificity [15].
  • Diazepam increased head dipping and locomotion equivalently in both lines of mice, but methamphetamine stimulated locomotion in HEB mice more than in LEB mice [3].

Regulatory relationships of Tcf12

  • The Id1 protein was found to repress ALF1 activity in vitro and in vivo [16].
  • Here we have shown that TAL1 and the ubiquitously expressed murine bHLH transcription factor ALF1 formed heterodimers that, compared with ALF1 homodimers, had a more restricted E-box specificity and bound preferentially to the glucocorticoid-responsive E-box (Egre) motif (AACAGATGGT) [17].

Other interactions of Tcf12

  • We have identified seven lambda clones expressing DNA-binding proteins representing two different genes termed ALF1 and ALF2 [9].
  • We observed extensive overlap in Id expression, especially in Schwann cell precursors that co-expressed all four Id proteins and REB [18].
  • Our results show that ALF1 may serve as a dimerization partner for the bHLH oncoprotein TAL1 and form a complex with a distinctive DNA binding property [17].
  • Gel mobility shift assays using NIH 3T3 nuclear extracts revealed that the upstream stimulatory factor, known as an E-box-binding protein, binds to these sites [19].

Analytical, diagnostic and therapeutic context of Tcf12

  • Northern blot analysis revealed that 1.3kb ME1 mRNA is highly expressed in the mouse epididymis [14].
  • The cells were analyzed by flow cytometry with a panel of four anti-B27 mAb: ME1, GSP5.3, GS145.2, and B27M2 [20].
  • These findings suggest that the ME1 single-chain antibody may be useful as a tool for clarifying the role of mutant p53 in tumor transformation, especially in cells heterozygous in p53, and possibly for gene therapy of tumors [21].
  • Transfectants were analyzed using specific PCR, RT-PCR and intracellular and extracellular staining with anti-HLA-B27 monoclonal antibody ME1 [22].
  • The hydroethanolic extract of the leaves (HEL) and bark (HEB) obtained from Alchornea castaneaefolia (Euphorbiaceae) were investigated for their ability to prevent ulceration of the gastric mucosa in animal models [23].


  1. Basic helix-loop-helix proteins in murine type C retrovirus transcriptional regulation. Nielsen, A.L., Pallisgaard, N., Pedersen, F.S., Jørgensen, P. J. Virol. (1994) [Pubmed]
  2. Resistance to growth of the Moloney lymphoma YAC in semi-syngeneic graft recipients. Ahrlund-Richter, L., Klein, E. Int. J. Cancer (1988) [Pubmed]
  3. Pharmacological and genetic influences on hole-board behaviors in mice. Kliethermes, C.L., Crabbe, J.C. Pharmacol. Biochem. Behav. (2006) [Pubmed]
  4. Tissue-specific RNA splicing generates an ankyrin-like domain that affects the dimerization and DNA-binding properties of a bHLH protein. Klein, E.S., Simmons, D.M., Swanson, L.W., Rosenfeld, M.G. Genes Dev. (1993) [Pubmed]
  5. The chromatin remodeler Mi-2beta is required for CD4 expression and T cell development. Williams, C.J., Naito, T., Arco, P.G., Seavitt, J.R., Cashman, S.M., De Souza, B., Qi, X., Keables, P., Von Andrian, U.H., Georgopoulos, K. Immunity (2004) [Pubmed]
  6. Helix-loop-helix proteins regulate pre-TCR and TCR signaling through modulation of Rel/NF-kappaB activities. Kim, D., Xu, M., Nie, L., Peng, X.C., Jimi, E., Voll, R.E., Nguyen, T., Ghosh, S., Sun, X.H. Immunity (2002) [Pubmed]
  7. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. Rivera, R.R., Johns, C.P., Quan, J., Johnson, R.S., Murre, C. Immunity (2000) [Pubmed]
  8. Expression of the bHLH transcription factor Tcf12 (ME1) gene is linked to the expansion of precursor cell populations during neurogenesis. Uittenbogaard, M., Chiaramello, A. Brain Res. Gene Expr. Patterns (2002) [Pubmed]
  9. Murine helix-loop-helix transcriptional activator proteins binding to the E-box motif of the Akv murine leukemia virus enhancer identified by cDNA cloning. Nielsen, A.L., Pallisgaard, N., Pedersen, F.S., Jørgensen, P. Mol. Cell. Biol. (1992) [Pubmed]
  10. Functional replacement of the mouse E2A gene with a human HEB cDNA. Zhuang, Y., Barndt, R.J., Pan, L., Kelley, R., Dai, M. Mol. Cell. Biol. (1998) [Pubmed]
  11. B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Zhuang, Y., Cheng, P., Weintraub, H. Mol. Cell. Biol. (1996) [Pubmed]
  12. Interplay of the E box, the cyclic AMP response element, and HTF4/HEB in transcriptional regulation of the neurospecific, neurotrophin-inducible vgf gene. Di Rocco, G., Pennuto, M., Illi, B., Canu, N., Filocamo, G., Trani, E., Rinaldi, A.M., Possenti, R., Mandolesi, G., Sirinian, M.I., Jucker, R., Levi, A., Nasi, S. Mol. Cell. Biol. (1997) [Pubmed]
  13. Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene. Grumont, R.J., Rasko, J.E., Strasser, A., Gerondakis, S. Mol. Cell. Biol. (1996) [Pubmed]
  14. Primary structure, genomic organization and expression of the major secretory protein of murine epididymis, ME1. Nakamura, Y., Takayama, N., Minamitani, T., Ikuta, T., Ariga, H., Matsumoto, K. Gene (2000) [Pubmed]
  15. Specificity of two anti-class I HLA monoclonal antibodies that block class I recognition by the NKB1 killer cell inhibitory receptor. Gumperz, J.E., Paterson, J.C., Litwin, V., Valiante, N., Lanier, L.L., Parham, P., Little, A.M. Tissue Antigens (1996) [Pubmed]
  16. Various modes of basic helix-loop-helix protein-mediated regulation of murine leukemia virus transcription in lymphoid cell lines. Nielsen, A.L., Nørby, P.L., Pedersen, F.S., Jørgensen, P. J. Virol. (1996) [Pubmed]
  17. E-box sequence and context-dependent TAL1/SCL modulation of basic helix-loop-helix protein-mediated transcriptional activation. Nielsen, A.L., Norby, P.L., Pedersen, F.S., Jorgensen, P. J. Biol. Chem. (1996) [Pubmed]
  18. Helix-loop-helix proteins in Schwann cells: a study of regulation and subcellular localization of Ids, REB, and E12/47 during embryonic and postnatal development. Stewart, H.J., Zoidl, G., Rossner, M., Brennan, A., Zoidl, C., Nave, K.A., Mirsky, R., Jessen, K.R. J. Neurosci. Res. (1997) [Pubmed]
  19. Cloning and characterization of the 5'-upstream sequence governing the cell cycle-dependent transcription of mouse DNA polymerase alpha 68 kDa subunit gene. Nishikawa, N.S., Izumi, M., Uchida, H., Yokoi, M., Miyazawa, H., Hanaoka, F. Nucleic Acids Res. (2000) [Pubmed]
  20. In vitro mutagenesis of HLA-B27: single and multiple amino acid substitutions at consensus B27 sites identify distinct monoclonal antibody-defined epitopes. el-Zaatari, F.A., Taurog, J.D. Hum. Immunol. (1992) [Pubmed]
  21. Single-chain antibody against the common epitope of mutant p53: isolation and intracytosolic expression in mammalian cells. Govorko, D., Cohen, G., Solomon, B. J. Immunol. Methods (2001) [Pubmed]
  22. The genetically-engineered secretory B27/Q10 chimeric molecule inhibits HLA-B27 restricted alloreactive T-lymphocytes. Kuipers, J.G., Bialowons, A., Dollmann, P., Jendro, M.C., Wagener, N., Rebmann, V., Ikeda, M., Huang, F., Grosse-Wilde, H., Yu, D.T., Zeidler, H., Märker-Hermann, E. Clinical and experimental rheumatology. (2002) [Pubmed]
  23. Antiulcerogenic activity of Alchornea castaneaefolia: effects on somatostatin, gastrin and prostaglandin. Hiruma-Lima, C.A., Calvo, T.R., Rodrigues, C.M., Andrade, F.D., Vilegas, W., Brito, A.R. Journal of ethnopharmacology. (2006) [Pubmed]
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