Large Maf Transcription Factors: Cousins of AP-1 Proteins and Important Regulators of Cellular Differentiation

A large number of mammalian transcription factors possess the evolutionary conserved basic and leucine zipper domain (bZIP). The basic domain interacts with DNA while the leucine zipper facilitates homo- and hetero- dimerization. These factors can be grouped into at least seven families: AP-1, ATF/CREB, CNC, C/EBP, Maf, PAR, and virus-encoded bZIPs. Here, we focus on a group of four large Maf proteins: MafA, MafB, c-Maf, and NRL. They act as key regulators of terminal differentiation in many tissues such as bone, brain, kidney, lens, pancreas, and retina, as well as in blood. The DNA-binding mechanism of large Mafs involves cooperation between the basic domain and an adjacent ancillary DNA-binding domain. Many genes regulated by Mafs during cellular differentiation use functional interactions between the Pax/Maf, Sox/Maf, and Ets/Maf promoter and enhancer modules. The prime examples are crystallin genes in lens and glucagon and insulin in pancreas. Novel roles for large Mafs emerged from studying generations of MafA and MafB knockouts and analysis of combined phenotypes in double or triple null mice. In addition, studies of this group of factors in invertebrates revealed the evolutionarily conserved function of these genes in the development of multicellular organisms.

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Identification of a novel determinant for basic domain-leucine zipper DNA binding activity in the acute-phase inducible nuclear factor-interleukin-6 transcription factor.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)34066-8 ◽

1994 ◽

Vol 269 (14) ◽

pp. 10341-10351

Author(s):

A.R. Brasier ◽

A. Kumar

Keyword(s):

Transcription Factor ◽

Dna Binding ◽

Acute Phase ◽

Interleukin 6 ◽

Leucine Zipper ◽

Binding Activity ◽

Nuclear Factor ◽

Basic Domain ◽

Dna Binding Activity

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Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain

Biochemical Journal ◽

10.1042/bj20070796 ◽

2007 ◽

Vol 408 (1) ◽

pp. 69-77 ◽

Cited By ~ 24

Author(s):

Ulrike Böer ◽

Julia Eglins ◽

Doris Krause ◽

Susanne Schnell ◽

Christof Schöfl ◽

...

Keyword(s):

Dna Binding ◽

Gene Transcription ◽

Leucine Zipper ◽

Luciferase Reporter ◽

Lithium Salts ◽

Transactivation Domain ◽

Camp Response Element ◽

Basic Leucine Zipper ◽

Response Element ◽

Leucine Zipper Domain

The molecular mechanism of the action of lithium salts in the treatment of bipolar disorder is not well understood. As their therapeutic action requires chronic treatment, adaptive neuronal processes are suggested to be involved. The molecular basis of this are changes in gene expression regulated by transcription factors such as CREB (cAMP-response-element-binding protein). CREB contains a transactivation domain, in which Ser119 is phosphorylated upon activation, and a bZip (basic leucine zipper domain). The bZip is involved in CREB dimerization and DNA-binding, but also contributes to CREB transactivation by recruiting the coactivator TORC (transducer of regulated CREB). In the present study, the effect of lithium on CRE (cAMP response element)/CREB-directed gene transcription was investigated. Electrically excitable cells were transfected with CRE/CREB-driven luciferase reporter genes. LiCl (6 mM or higher) induced an up to 4.7-fold increase in 8-bromo-cAMP-stimulated CRE/CREB-directed transcription. This increase was not due to enhanced Ser119 phosphorylation or DNA-binding of CREB. Also, the known targets inositol monophosphatase and GSK3β (glycogen-synthase-kinase 3β) were not involved as specific GSK3β inhibitors and inositol replenishment did not mimic and abolish respectively the effect of lithium. However, lithium no longer enhanced CREB activity when the CREB-bZip was deleted or the TORC-binding site inside the CREB-bZip was specifically mutated (CREB-R300A). Otherwise, TORC overexpression conferred lithium responsiveness on CREB-bZip or the CRE-containing truncated rat somatostatin promoter. This indicates that lithium enhances cAMP-induced CRE/CREB-directed transcription, conferred by TORC on the CREB-bZip. We thus support the hypothesis that lithium salts modulate CRE/CREB-dependent gene transcription and suggest the CREB coactivator TORC as a new molecular target of lithium.

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c-Jun Homodimers Can Function as a Context-Specific Coactivator

Molecular and Cellular Biology ◽

10.1128/mcb.00936-06 ◽

2007 ◽

Vol 27 (8) ◽

pp. 2919-2933 ◽

Cited By ~ 33

Author(s):

Benoit Grondin ◽

Martin Lefrancois ◽

Mathieu Tremblay ◽

Marianne Saint-Denis ◽

André Haman ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Dna Binding ◽

Rna Polymerase Ii ◽

Protein Interactions ◽

Expression Profiles ◽

Basic Domain ◽

Interaction Mode

ABSTRACT Transcription factors can function as DNA-binding-specific activators or as coactivators. c-Jun drives gene expression via binding to AP-1 sequences or as a cofactor for PU.1 in macrophages. c-Jun heterodimers bind AP-1 sequences with higher affinity than homodimers, but how c-Jun works as a coactivator is unknown. Here, we provide in vitro and in vivo evidence that c-Jun homodimers are recruited to the interleukin-1β (IL-1β) promoter in the absence of direct DNA binding via protein-protein interactions with DNA-anchored PU.1 and CCAAT/enhancer-binding protein β (C/EBPβ). Unexpectedly, the interaction interface with PU.1 and C/EBPβ involves four of the residues within the basic domain of c-Jun that contact DNA, indicating that the capacities of c-Jun to function as a coactivator or as a DNA-bound transcription factor are mutually exclusive. Our observations indicate that the IL-1β locus is occupied by PU.1 and C/EBPβ and poised for expression and that c-Jun enhances transcription by facilitating a rate-limiting step, the assembly of the RNA polymerase II preinitiation complex, with minimal effect on the local chromatin status. We propose that the basic domain of other transcription factors may also be redirected from a DNA interaction mode to a protein-protein interaction mode and that this switch represents a novel mechanism regulating gene expression profiles.

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Phosphorylation of BATF regulates DNA binding: a novel mechanism for AP-1 (activator protein-1) regulation

Biochemical Journal ◽

10.1042/bj20030455 ◽

2003 ◽

Vol 374 (2) ◽

pp. 423-431 ◽

Cited By ~ 26

Author(s):

Christopher D. DEPPMANN ◽

Tina M. THORNTON ◽

Fransiscus E. UTAMA ◽

Elizabeth J. TAPAROWSKY

Keyword(s):

Transcription Factors ◽

Dna Binding ◽

Leucine Zipper ◽

Binding Domain ◽

Dna Binding Domain ◽

Activator Protein 1 ◽

Basic Leucine Zipper ◽

Activator Protein

BATF is a member of the AP-1 (activator protein-1) family of bZIP (basic leucine zipper) transcription factors that form transcriptionally inhibitory, DNA binding heterodimers with Jun proteins. In the present study, we demonstrate that BATF is phosphorylated in vivo on multiple serine and threonine residues and at least one tyrosine residue. Reverse-polarity PAGE revealed that serine-43 and threonine-48 within the DNA binding domain of BATF are phosphorylated. To model phosphorylation of the BATF DNA binding domain, serine-43 was replaced by an aspartate residue. BATF(S43D) retains the ability to dimerize with Jun proteins in vitro and in vivo, and the BATF(S43D):Jun heterodimer localizes properly to the nucleus of cells. Interestingly, BATF(S43D) functions like wild-type BATF to reduce AP-1-mediated gene transcription, despite the observed inability of the BATF(S43D):Jun heterodimer to bind DNA. These data demonstrate that phosphorylation of serine-43 converts BATF from a DNA binding into a non-DNA binding inhibitor of AP-1 activity. Given that 40% of mammalian bZIP transcription factors contain a residue analogous to serine-43 of BATF in their DNA binding domains, the phosphorylation event described here represents a mechanism that is potentially applicable to the regulation of many bZIP proteins.

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Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation.

Molecular and Cellular Biology ◽

10.1128/mcb.13.2.841 ◽

1993 ◽

Vol 13 (2) ◽

pp. 841-851 ◽

Cited By ~ 114

Author(s):

K A Lord ◽

A Abdollahi ◽

B Hoffman-Liebermann ◽

D A Liebermann

Keyword(s):

Transcription Factors ◽

Leucine Zipper ◽

Culture Media ◽

Terminal Differentiation ◽

Cell Types ◽

Primary Response ◽

Myeloid Differentiation ◽

Active Transcription

The proto-oncogenes c-jun, junB, junD, and c-fos recently have been shown to encode for transcription factors with a leucine zipper that mediates dimerization to constitute active transcription factors; juns were shown to dimerize with each other and with c-fos, whereas fos was shown to dimerize only with juns. After birth, hematopoietic cells of the myeloid lineage, and some other terminally differentiated cell types, express high levels of c-fos. Still, the role of fos/jun transcription factors in normal myelopoiesis or in leukemogenesis has not been established. Recently, c-jun, junB, and junD were identified as myeloid differentiation primary response genes stably expressed following induction of terminal differentiation of myeloblastic leukemia M1 cells. Intriguingly, c-fos, though induced during normal myelopoiesis, was not induced upon M1 differentiation. To gain further insights into the role of fos/jun in normal myelopoiesis and leukemogenicity, M1fos and M1junB cell lines, which constitutively express c-fos and junB, respectively, were established. It was shown that enforced expression of c-fos, and to a lesser extent junB, in M1 cells results in both an increased propensity to differentiate and a reduction in the aggressiveness of the M1 leukemic phenotype. M1fos cells constitutively expressed immediate-early and late genetic markers of differentiated M1 cells. The in vitro differentiation of normal myeloblasts into mature macrophages and granulocytes, as well as the increased propensity of M1fos leukemic myeloblasts to be induced for terminal differentiation, was dramatically impaired with use of c-fos antisense oligomers in the culture media. Taken together, these observations show that the proto-oncogenes which encode for fos/jun transcription factors play important roles in promoting myeloid differentiation. The ability of the M1 leukemic myeloblasts to be induced for terminal differentiation in the absence of apparent fos expression indicates that there is some redundancy among the fos/jun family of transcription factors in promoting myeloid differentiation; however, juns alone cannot completely compensate for the lack of fos. Thus, genetic lesions affecting fos/jun expression may play a role in the development of "preleukemic" myelodysplastic syndromes and their further progression to leukemias.

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Synchronization and interaction of proline, ascorbate and oxidative stress pathways under abiotic stress combination in tomato plants

10.1101/2020.06.30.179770 ◽

2020 ◽

Author(s):

María Lopez-Delacalle ◽

Christian J Silva ◽

Teresa C Mestre ◽

Vicente Martinez ◽

Barbara Blanco-Ulate ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factors ◽

Metabolic Pathways ◽

Leucine Zipper ◽

Redox Homeostasis ◽

Basic Leucine Zipper ◽

Cellular Redox ◽

Tomato Plants ◽

Leucine Zipper Domain ◽

And Oxidative Stress

ABSTRACTAdverse environmental conditions have a devastating impact on plant productivity. In nature, multiple abiotic stresses occur simultaneously, and plants have evolved unique responses to cope against this combination of stresses. Here, we coupled genome-wide transcriptional profiling and untargeted metabolomics with physiological and biochemical analyses to characterize the effect of salinity and heat applied in combination on the metabolism of tomato plants. Our results demonstrate that this combination of stresses causes a unique reprogramming of metabolic pathways, including changes in the expression of 1,388 genes and the accumulation of 568 molecular features. Pathway enrichment analysis of transcript and metabolite data indicated that the proline and ascorbate pathways act synchronously to maintain cellular redox homeostasis, which was supported by measurements of enzymatic activity and oxidative stress markers. We also identified key transcription factors from the basic Leucine Zipper Domain (bZIP), Zinc Finger Cysteine-2/Histidine-2 (C2H2) and Trihelix families that are likely regulators of the identified up-regulated genes under salinity+heat combination. Our results expand the current understanding of how plants acclimate to environmental stresses in combination and unveils the synergy between key cellular metabolic pathways for effective ROS detoxification. Our study opens the door to elucidating the different signaling mechanisms for stress tolerance.HIGHLIGHTSThe combination of salinity and heat causes a unique reprogramming of tomato metabolic pathways by changing the expression of specific genes and metabolic features.Proline and ascorbate pathways act synchronously to maintain cellular redox homeostasisKey transcription factors from the basic Leucine Zipper Domain (bZIP), Zinc Finger Cysteine-2/Histidine-2 (C2H2) and Trihelix families were identified as putative regulators of the identified up-regulated genes under salinity and heat combination.

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Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site.

Molecular and Cellular Biology ◽

10.1128/mcb.16.11.6083 ◽

1996 ◽

Vol 16 (11) ◽

pp. 6083-6095 ◽

Cited By ~ 407

Author(s):

T Oyake ◽

K Itoh ◽

H Motohashi ◽

N Hayashi ◽

H Hoshino ◽

...

Keyword(s):

Transcription Factors ◽

Dna Binding ◽

Leucine Zipper ◽

Basic Leucine Zipper ◽

Significant Similarity ◽

Btb Domain ◽

Binding Forms ◽

Bzip Domain ◽

Bzip Proteins

Members of the small Maf family (MafK, MafF, and MafG) are basic region leucine zipper (bZip) proteins that can function as transcriptional activators or repressors. The dimer compositions of their DNA binding forms determine whether the small Maf family proteins activate or repress transcription. Using a yeast two-hybrid screen with a GAL4-MafK fusion protein, we have identified two novel bZip transcription factors, Bach1 and Bach2, as heterodimerization partners of MafK. In addition to a Cap'n'collar-type bZip domain, these Bach proteins possess a BTB domain which is a protein interaction motif; Bach1 and Bach2 show significant similarity to each other in these regions but are otherwise divergent. Whereas expression of Bach1 appears ubiquitous, that of Bach2 is restricted to monocytes and neuronal cells. Bach proteins bind in vitro to NF-E2 binding sites, recognition elements for the hematopoietic transcription factor NF-E2, by forming heterodimers with MafK. Furthermore, a DNA binding complex that contained MafK as well as Bach2 or a protein related closely to Bach2 was found to be present in mouse brain cells. Bach1 and Bach2 function as transcription repressors in transfection assays using fibroblast cells, but they function as a transcriptional activator and repressor, respectively, in cultured erythroid cells. The results suggest that members of the Bach family play important roles in coordinating transcription activation and repression by MafK.

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