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Gene Review

HEXIM1  -  hexamethylene bis-acetamide inducible 1

Homo sapiens

Synonyms: CLP-1, CLP1, Cardiac lineage protein 1, EDG1, Estrogen down-regulated gene 1 protein, ...
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Disease relevance of HEXIM1

  • Binding of HEXIM1 is a prerequisite for association of P-TEFb with the G302-C324 apical region of the 3' hairpin of 7SK that is highly reminiscent of the human immunodeficiency virus transactivation-responsive RNA [1].
  • A major portion of nuclear P-TEFb is sequestered and inactivated by the coordinated actions of the 7SK snRNA and the HEXIM1 protein, whose induced dissociation from P-TEFb is crucial for stress-induced transcription and pathogenesis of cardiac hypertrophy [2].
  • We found that HEXIM1 mRNA and protein levels are up-regulated during differentiation of murine erythroleukemia cells upon treatment with HMBA or DMSO [3].
  • These studies support a role for EDG1 in breast cancer [4].
  • Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat [5].

High impact information on HEXIM1

  • Using a human CD25 reporter transgene controlled by regulatory sequences from the gene encoding pre-T cell receptor alpha, we identified a common lymphocyte precursor (CLP-2) population that, in contrast to the previously identified CLP-1 population, was c-Kit-B220+ [6].
  • In short-term culture, the CLP-2 could be derived from the CLP-1 subset, and contained cells that in clonogenic assays were assessed to be bipotent precursors of T and B cells [6].
  • In stress-induced cells, the 7SK/HEXIM1-bound P-TEFb is quantitatively converted into the Brd4-associated form [7].
  • Since HEXIM1 expression is induced in cells treated with hexamethylene bisacetamide, a potent inducer of cell differentiation, targeting the general transcription factor P-TEFb by HEXIM1/7SK may contribute to the global control of cell growth and differentiation [8].
  • The removal of the positive or negative charges from these regions in HEXIM1 leads to its sequestration into the large complex and inhibition of transcription independently of the arginine-rich motif [9].

Chemical compound and disease context of HEXIM1

  • In CHO-AGR16 cells, but not in parental CHO cells, S1P stimulated the production of inositol phosphates and Ca2+ mobilization which was only 30% inhibited by pertussis toxin (PTX), different from the case of the recently identified S1P receptor EDG1 [10].

Biological context of HEXIM1

  • Introduction of HEXIM1 short interfering RNA and adenovirus-mediated exogenous expression of HEXIM1 positively and negatively modulated glucocorticoid-responsive gene activation, respectively [11].
  • The HEXIM1 protein, aided by the 7SK snRNA, sequesters P-TEFb into an inactive 7SK.HEXIM1.P-TEFb small nuclear ribonucleic acid particle for inhibition of transcription and, consequently, cell proliferation [12].
  • We found that the basic region in HEXIM1 directs its nuclear import via two monopartite and two bipartite nuclear localization sequences [9].
  • We demonstrate that two structurally and functionally distinct protein binding elements located in the 5'- and 3'-terminal hairpins of 7SK support the in vivo recruitment of HEXIM1 and P-TEFb [1].
  • Stimulation of HEXIM1 is not restricted to hematopoietic cells, as induction of phenotypic differentiation of neuroblastoma cells by retinoic acid results in up-regulation of HEXIM1 [3].

Anatomical context of HEXIM1


Associations of HEXIM1 with chemical compounds


Physical interactions of HEXIM1

  • It is proposed that 7SK RNA binding to a HEXIM1 multimer promotes the simultaneous recruitment and hence inactivation of multiple P-TEFb units [17].
  • According to yeast two-hybrid analysis and immunoprecipitations from extracts of transfected cells, MAQ1 binds directly to the N-terminal cyclin homology region of cyclins T1 and T2 [20].
  • Functional assays in HeLa cells showed that this cyclin T-binding domain (TBD) is required for the binding of Hexim1 to P-TEFb and inhibition of transcriptional activity in vivo [5].

Regulatory relationships of HEXIM1

  • Deletion of the first 121 amino acids of HEXIM1 allowed it to inhibit P-TEFb partially in the absence of 7SK RNA [18].
  • Not only the exogenously expressed but also IFN-gamma-induced CIITA was inhibited by Hexim1 [21].

Other interactions of HEXIM1


Analytical, diagnostic and therapeutic context of HEXIM1

  • The CLP-1 gene promoter is active in different cell types and sequence analysis shows a number of potential binding sites for cardiogenic transcription factors such as Nkx2.5 and GATA-4, indicating a potential role in development [23].


  1. Regulation of polymerase II transcription by 7SK snRNA: two distinct RNA elements direct P-TEFb and HEXIM1 binding. Egloff, S., Van Herreweghe, E., Kiss, T. Mol. Cell. Biol. (2006) [Pubmed]
  2. Phosphorylated positive transcription elongation factor b (P-TEFb) is tagged for inhibition through association with 7SK snRNA. Chen, R., Yang, Z., Zhou, Q. J. Biol. Chem. (2004) [Pubmed]
  3. Increased HEXIM1 expression during erythroleukemia and neuroblastoma cell differentiation. Turano, M., Napolitano, G., Dulac, C., Majello, B., Bensaude, O., Lania, L. J. Cell. Physiol. (2006) [Pubmed]
  4. Identification of a novel inhibitor of breast cell growth that is down-regulated by estrogens and decreased in breast tumors. Wittmann, B.M., Wang, N., Montano, M.M. Cancer Res. (2003) [Pubmed]
  5. Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat. Schulte, A., Czudnochowski, N., Barboric, M., Schönichen, A., Blazek, D., Peterlin, B.M., Geyer, M. J. Biol. Chem. (2005) [Pubmed]
  6. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Martin, C.H., Aifantis, I., Scimone, M.L., von Andrian, U.H., Reizis, B., von Boehmer, H., Gounari, F. Nat. Immunol. (2003) [Pubmed]
  7. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Yang, Z., Yik, J.H., Chen, R., He, N., Jang, M.K., Ozato, K., Zhou, Q. Mol. Cell (2005) [Pubmed]
  8. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Yik, J.H., Chen, R., Nishimura, R., Jennings, J.L., Link, A.J., Zhou, Q. Mol. Cell (2003) [Pubmed]
  9. Interplay between 7SK snRNA and oppositely charged regions in HEXIM1 direct the inhibition of P-TEFb. Barboric, M., Kohoutek, J., Price, J.P., Blazek, D., Price, D.H., Peterlin, B.M. EMBO J. (2005) [Pubmed]
  10. The novel sphingosine 1-phosphate receptor AGR16 is coupled via pertussis toxin-sensitive and -insensitive G-proteins to multiple signalling pathways. Gonda, K., Okamoto, H., Takuwa, N., Yatomi, Y., Okazaki, H., Sakurai, T., Kimura, S., Sillard, R., Harii, K., Takuwa, Y. Biochem. J. (1999) [Pubmed]
  11. HEXIM1 forms a transcriptionally abortive complex with glucocorticoid receptor without involving 7SK RNA and positive transcription elongation factor b. Shimizu, N., Ouchida, R., Yoshikawa, N., Hisada, T., Watanabe, H., Okamoto, K., Kusuhara, M., Handa, H., Morimoto, C., Tanaka, H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription. Yik, J.H., Chen, R., Pezda, A.C., Zhou, Q. J. Biol. Chem. (2005) [Pubmed]
  13. HEXIM2, a HEXIM1-related protein, regulates positive transcription elongation factor b through association with 7SK. Byers, S.A., Price, J.P., Cooper, J.J., Li, Q., Price, D.H. J. Biol. Chem. (2005) [Pubmed]
  14. siRNA depletion of 7SK snRNA induces apoptosis but does not affect expression of the HIV-1 LTR or P-TEFb-dependent cellular genes. Haaland, R.E., Herrmann, C.H., Rice, A.P. J. Cell. Physiol. (2005) [Pubmed]
  15. Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4+ T cells. Sung, T.L., Rice, A.P. Retrovirology (2006) [Pubmed]
  16. Suppression of NF-kappaB-dependent gene expression by a hexamethylene bisacetamide-inducible protein HEXIM1 in human vascular smooth muscle cells. Ouchida, R., Kusuhara, M., Shimizu, N., Hisada, T., Makino, Y., Morimoto, C., Handa, H., Ohsuzu, F., Tanaka, H. Genes Cells (2003) [Pubmed]
  17. Transcription-dependent association of multiple positive transcription elongation factor units to a HEXIM multimer. Dulac, C., Michels, A.A., Fraldi, A., Bonnet, F., Nguyen, V.T., Napolitano, G., Lania, L., Bensaude, O. J. Biol. Chem. (2005) [Pubmed]
  18. Analysis of the large inactive P-TEFb complex indicates that it contains one 7SK molecule, a dimer of HEXIM1 or HEXIM2, and two P-TEFb molecules containing Cdk9 phosphorylated at threonine 186. Li, Q., Price, J.P., Byers, S.A., Cheng, D., Peng, J., Price, D.H. J. Biol. Chem. (2005) [Pubmed]
  19. Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Liu, C.H., Thangada, S., Lee, M.J., Van Brocklyn, J.R., Spiegel, S., Hla, T. Mol. Biol. Cell (1999) [Pubmed]
  20. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Michels, A.A., Nguyen, V.T., Fraldi, A., Labas, V., Edwards, M., Bonnet, F., Lania, L., Bensaude, O. Mol. Cell. Biol. (2003) [Pubmed]
  21. Hexim1 sequesters positive transcription elongation factor b from the class II transactivator on MHC class II promoters. Kohoutek, J., Blazek, D., Peterlin, B.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  22. Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. Michels, A.A., Fraldi, A., Li, Q., Adamson, T.E., Bonnet, F., Nguyen, V.T., Sedore, S.C., Price, J.P., Price, D.H., Lania, L., Bensaude, O. EMBO J. (2004) [Pubmed]
  23. Structure, expression, and functional characterization of the mouse CLP-1 gene. Huang, F., Wagner, M., Siddiqui, M.A. Gene (2002) [Pubmed]
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