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Gene Review

CREB3  -  cAMP responsive element binding protein 3

Homo sapiens

Synonyms: CREB-3, Cyclic AMP-responsive element-binding protein 3, LUMAN, LZIP, Leucine zipper protein, ...
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Disease relevance of CREB3

  • Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor [1].
  • Interestingly, Luman could activate the promoters of IE110 and LAT, two genes that are critical for reactivation of HSV-1 from latency [2].
  • Our objective is to explore interactions between Luman and HCF and to determine if they play a role in the biology of herpesviruses [2].
  • Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation [3].

High impact information on CREB3

  • VP16 and LZIP share a tetrapeptide motif-D/EHXY-used to associate with human HCF [4].
  • This bZIP factor, designated LZIP, activates CRE-dependent transcription and regulates cell proliferation [3].
  • Loss of LZIP function in NIH 3T3 cells triggers morphological transformation and anchorage-independent growth [3].
  • Luman/CREB3 Induces Transcription of the Endoplasmic Reticulum (ER) Stress Response Protein Herp through an ER Stress Response Element [5].
  • LUMAN is activated in dendritic cells, the professional antigen-presenting cells of the immune system, upon TLR signaling, and likely plays a role in early immune responses [6].
  • The activation of LUMAN in dendritic cells likely involves also DC-STAMP and OS-9, both of which bind physically to LUMAN at the cytosolic side of the ER [6].

Biological context of CREB3


Anatomical context of CREB3

  • Luman appears to be a ubiquitous transcription factor, and its mRNA was detected in all human adult and fetal tissues examined [1].
  • This cytoplasmic association of Luman and HCF could also be demonstrated in neurons in trigeminal ganglia removed from cattle soon after death [2].
  • Luman/CREB3 (also called LZIP) is an endoplasmic reticulum (ER) membrane-bound transcription factor which is believed to undergo regulated intramembrane proteolysis in response to cellular cues [5].
  • Luman conforms to a type II membrane-associated glycoprotein with its carboxyl terminus embedded in cellular membranes and its amino terminus, which contains all its identified functional domains, in the cytoplasm [9].
  • We observed that following S1P cleavage, the majority of the cleaved Luman was retained in cytoplasmic membranes, indicating that an additional step or enzymes yet to be identified are involved in complete cleavage and release to yield the product which ultimately enters the nuclei of cells [9].

Associations of CREB3 with chemical compounds

  • Thus, processing of Luman was highly stimulated by brefeldin A, a compound that causes the reflux of Golgi apparatus enzymes to the endoplasmic reticulum (ER) [9].
  • Substitution of arginine residues within this motif abolished S1P cleavage, providing robust evidence that S1P is involved in Luman processing [9].
  • We also find that ATF6's luminal domain is sufficient to sense ER stress and cause translocation to the Golgi when fused to LZIP, another ER transmembrane protein [10].
  • Unlike ATF6, however, Luman was not activated by proteolytic cleavage in response to endoplasmic reticulum stressors such as tunicamycin and thapsigargin [11].
  • Fifteen patients were investigated: 5 of 15 patients developed abnormal lactate metabolism on atrial pacing (change greater than 0.8 mg per cent in A/V lactate difference) and all had greater than 50 per cent coronary luman reduction after E [12].

Physical interactions of CREB3

  • Luman and VP16 appear to have similar mechanisms for binding HCF, as in vitro each competitively inhibited the binding of the other to HCF [1].
  • HCLP-1 selectively interacts with LZIP but not with VP16 [13].
  • These data indicate that LZIP binds to CCR1 and that the interaction between CCR1 and LZIP participates in regulation of Lkn-1-dependent cell migration without affecting the chemotactic activities of other CC chemokines that bind to CCR1 [14].
  • LUMAN binds to DC-STAMP, as determined by yeast two-hybrid assays and co-immunoprecipitation analysis [6].
  • LUMAN binds to OS-9, as determined by co-immunoprecipitation analysis [6].

Regulatory relationships of CREB3

  • Importantly, with several of the mutants we observe a poor correlation between the ability to associate with LZIP and promote cell proliferation in the context of the full HCF-1 amino terminus, arguing that the HCF-1 beta-propeller domain must target other cellular transcription factors in order to contribute to G(1) progression [7].
  • Results from an inhibitor assay showed that NF-kappaB is involved in Lkn-1-induced LZIP expression, but Sp-1 is not [15].

Other interactions of CREB3

  • Unlike Luman, or most other bZIP proteins, ZF by itself did not appear to bind consensus bZIP-binding sites [8].
  • Thus, HCLP-1 serves a transcriptional co-repressor function mediated through its inhibitory interaction with the LZIP transcription factor [13].
  • The absence of CRF-BP gene transcript in human ovarian follicles was confirmed by reverse transcription-PCR, indicating that the IrCRF-BP detected is not derived from the ovarian transcript and suggesting that the presence of IrCRF-BP and luman of capillary vessels in the thecal compartment originates from the peripheral circulation [16].

Analytical, diagnostic and therapeutic context of CREB3


  1. Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor. Lu, R., Yang, P., O'Hare, P., Misra, V. Mol. Cell. Biol. (1997) [Pubmed]
  2. Potential role for luman, the cellular homologue of herpes simplex virus VP16 (alpha gene trans-inducing factor), in herpesvirus latency. Lu, R., Misra, V. J. Virol. (2000) [Pubmed]
  3. Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation. Jin, D.Y., Wang, H.L., Zhou, Y., Chun, A.C., Kibler, K.V., Hou, Y.D., Kung, H., Jeang, K.T. EMBO J. (2000) [Pubmed]
  4. Viral mimicry: common mode of association with HCF by VP16 and the cellular protein LZIP. Freiman, R.N., Herr, W. Genes Dev. (1997) [Pubmed]
  5. Luman/CREB3 Induces Transcription of the Endoplasmic Reticulum (ER) Stress Response Protein Herp through an ER Stress Response Element. Liang, G., Audas, T.E., Li, Y., Cockram, G.P., Dean, J.D., Martyn, A.C., Kokame, K., Lu, R. Mol. Cell. Biol. (2006) [Pubmed]
  6. DC-STAMP interacts with ER-resident transcription factor LUMAN which becomes activated during DC maturation. Eleveld-Trancikova, D., Sanecka, A., van Hout-Kuijer, M.A., Looman, M.W., Hendriks, I.A., Jansen, B.J., Adema, G.J. Mol. Immunol. (2010) [Pubmed]
  7. Mutations in host cell factor 1 separate its role in cell proliferation from recruitment of VP16 and LZIP. Mahajan, S.S., Wilson, A.C. Mol. Cell. Biol. (2000) [Pubmed]
  8. Zhangfei: a second cellular protein interacts with herpes simplex virus accessory factor HCF in a manner similar to Luman and VP16. Lu, R., Misra, V. Nucleic Acids Res. (2000) [Pubmed]
  9. Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis. Raggo, C., Rapin, N., Stirling, J., Gobeil, P., Smith-Windsor, E., O'Hare, P., Misra, V. Mol. Cell. Biol. (2002) [Pubmed]
  10. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. Chen, X., Shen, J., Prywes, R. J. Biol. Chem. (2002) [Pubmed]
  11. Luman is capable of binding and activating transcription from the unfolded protein response element. DenBoer, L.M., Hardy-Smith, P.W., Hogan, M.R., Cockram, G.P., Audas, T.E., Lu, R. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  12. The pathophysiology of angina pectoris with normal coronary arteriograms. Histopathological and metabolic correlations with coronary vasospasm. Richardson, P.J., Rothman, M.T., Atkinson, L., Baadrup, U., Jackson, G. Archives des maladies du coeur et des vaisseaux. (1983) [Pubmed]
  13. Inhibition of LZIP-mediated transcription through direct interaction with a novel host cell factor-like protein. Zhou, H.J., Wong, C.M., Chen, J.H., Qiang, B.Q., Yuan, J.G., Jin, D.Y. J. Biol. Chem. (2001) [Pubmed]
  14. Human LZIP binds to CCR1 and differentially affects the chemotactic activities of CCR1-dependent chemokines. Ko, J., Jang, S.W., Kim, Y.S., Kim, I.S., Sung, H.J., Kim, H.H., Park, J.Y., Lee, Y.H., Kim, J., Na, D.S. FASEB J. (2004) [Pubmed]
  15. Regulation of human LZIP expression by NF-kappaB and its involvement in monocyte cell migration induced by Lkn-1. Jang, S.W., Kim, Y.S., Kim, Y.R., Sung, H.J., Ko, J. J. Biol. Chem. (2007) [Pubmed]
  16. Expression of genes encoding corticotropin-releasing factor (CRF), type 1 CRF receptor, and CRF-binding protein and localization of the gene products in the human ovary. Asakura, H., Zwain, I.H., Yen, S.S. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
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