The Functional Versatility of CREM is Determined by Its Modular Structure

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1993 Mar 1

PMID 8458330

Citations 51

Authors

B M Laoide

N S Foulkes

F Schlotter

P Sassone-Corsi

Affiliations

Soon will be listed here.

Abstract

The CREM gene (cAMP-responsive element modulator) generates both activators and repressors of cAMP-induced transcription by alternative splicing. We determined the exon structure of the CREM gene and have identified new isoforms. We show that CREM isoforms with different structural characteristics are generated by the shuffling of exons to produce proteins with various combinations of functional domains. CREM proteins bind efficiently to CREs and here we demonstrate that the various isoforms heterodimerize in vivo with each other and with CREB. The two alternative DNA binding domains of CREM, which are differentially spliced in the various isoforms, show distinct binding efficiencies, while CREM alpha/CREB heterodimers exhibit stronger binding than CREM beta/CREB heterodimers to a consensus CRE in vitro. We identify the protein domains involved in activation function and find that the phosphorylation domain and a single glutamine-rich domain are sufficient for activation. A minimal CREM repressor, containing only the b-Zip motif, efficiently antagonizes cAMP-induced transcription. In addition, phosphorylation may reduce repressor function, as a CREM beta mutant carrying a mutation of the serine phosphoacceptor site (CREM beta 68) represses more efficiently than the wild-type CREM beta.

Citing Articles

Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution.

Liu W, Jakobs J, Rink L Int J Mol Sci. 2023; 24(2).

PMID: 36674704 PMC: 9867219. DOI: 10.3390/ijms24021191.

Basic Leucine Zipper Transcription Factors as Important Regulators of Leydig Cells' Functions.

Martin L, Nguyen H Int J Mol Sci. 2022; 23(21).

PMID: 36361676 PMC: 9658026. DOI: 10.3390/ijms232112887.

Dual regulation of miR-375 and CREM genes in pancreatic beta cells.

Keller D, Perez I Islets. 2022; 14(1):139-148.

PMID: 35377267 PMC: 8986308. DOI: 10.1080/19382014.2022.2060688.

Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling.

Hall E, Pal S, Glennon M, Shridhar P, Satterfield S, Weber B Cardiovasc Res. 2021; 118(9):2124-2138.

PMID: 34329394 PMC: 9302887. DOI: 10.1093/cvr/cvab257.

Expression of Transcription Factor in Human Tissues.

Kaprio H, Heuser V, Orte K, Tukiainen M, Leivo I, Gardberg M J Histochem Cytochem. 2021; 69(8):495-509.

PMID: 34261344 PMC: 8329441. DOI: 10.1369/00221554211032008.

References

Rehfuss R, Walton K, Loriaux M, Goodman R . The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A. J Biol Chem. 1991; 266(28):18431-4. View

Borrelli E, Montmayeur J, Foulkes N, Sassone-Corsi P . Signal transduction and gene control: the cAMP pathway. Crit Rev Oncog. 1992; 3(4):321-38. View

Descombes P, Schibler U . A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell. 1991; 67(3):569-79. DOI: 10.1016/0092-8674(91)90531-3. View

Flint K, Jones N . Differential regulation of three members of the ATF/CREB family of DNA-binding proteins. Oncogene. 1991; 6(11):2019-26. View

Foulkes N, Mellstrom B, Benusiglio E, Sassone-Corsi P . Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature. 1992; 355(6355):80-4. DOI: 10.1038/355080a0. View

Waeber G, Meyer T, Lesieur M, HERMANN H, Gerard N, Habener J . Developmental stage-specific expression of cyclic adenosine 3',5'-monophosphate response element-binding protein CREB during spermatogenesis involves alternative exon splicing. Mol Endocrinol. 1991; 5(10):1418-30. DOI: 10.1210/mend-5-10-1418. View

Foulkes N, Sassone-Corsi P . More is better: activators and repressors from the same gene. Cell. 1992; 68(3):411-4. DOI: 10.1016/0092-8674(92)90178-f. View

Treacy M, Neilson L, Turner E, He X, Rosenfeld M . Twin of I-POU: a two amino acid difference in the I-POU homeodomain distinguishes an activator from an inhibitor of transcription. Cell. 1992; 68(3):491-505. DOI: 10.1016/0092-8674(92)90186-g. View

Ruppert S, Cole T, Boshart M, Schmid E, Schutz G . Multiple mRNA isoforms of the transcription activator protein CREB: generation by alternative splicing and specific expression in primary spermatocytes. EMBO J. 1992; 11(4):1503-12. PMC: 556599. DOI: 10.1002/j.1460-2075.1992.tb05195.x. View

10.

Delmas V, Laoide B, Masquilier D, de Groot R, Foulkes N, Sassone-Corsi P . Alternative usage of initiation codons in mRNA encoding the cAMP-responsive-element modulator generates regulators with opposite functions. Proc Natl Acad Sci U S A. 1992; 89(10):4226-30. PMC: 49054. DOI: 10.1073/pnas.89.10.4226. View

11.

Delegeane A, Ferland L, Mellon P . Tissue-specific enhancer of the human glycoprotein hormone alpha-subunit gene: dependence on cyclic AMP-inducible elements. Mol Cell Biol. 1987; 7(11):3994-4002. PMC: 368068. DOI: 10.1128/mcb.7.11.3994-4002.1987. View

12.

Landschulz W, Johnson P, McKnight S . The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988; 240(4860):1759-64. DOI: 10.1126/science.3289117. View

13.

Yamamoto K, Gonzalez G, Biggs 3rd W, Montminy M . Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988; 334(6182):494-8. DOI: 10.1038/334494a0. View

14.

Sassone-Corsi P . Cyclic AMP induction of early adenovirus promoters involves sequences required for E1A trans-activation. Proc Natl Acad Sci U S A. 1988; 85(19):7192-6. PMC: 282150. DOI: 10.1073/pnas.85.19.7192. View

15.

Courey A, Tjian R . Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell. 1988; 55(5):887-98. DOI: 10.1016/0092-8674(88)90144-4. View

16.

Hoeffler J, Meyer T, Yun Y, Jameson J, Habener J . Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science. 1988; 242(4884):1430-3. DOI: 10.1126/science.2974179. View

17.

Sassone-Corsi P, Visvader J, Ferland L, Mellon P, Verma I . Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. Genes Dev. 1988; 2(12A):1529-38. DOI: 10.1101/gad.2.12a.1529. View

18.

McKnight G, Clegg C, Uhler M, Chrivia J, Cadd G, Correll L . Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog Horm Res. 1988; 44:307-35. DOI: 10.1016/b978-0-12-571144-9.50014-4. View

19.

Gonzalez G, Yamamoto K, Fischer W, Karr D, Menzel P, Biggs 3rd W . A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence. Nature. 1989; 337(6209):749-52. DOI: 10.1038/337749a0. View

20.

Lillie J, Green M . Transcription activation by the adenovirus E1a protein. Nature. 1989; 338(6210):39-44. DOI: 10.1038/338039a0. View