Synergistic Transcription Activation by Maf and Sox and Their Subnuclear Localization Are Disrupted by a Mutation in Maf That Causes Cataract

Rajaram, Nirmala; Kerppola, Tom K.

doi:10.1128/mcb.24.13.5694-5709.2004

Cited by 49 publications

(30 citation statements)

References 52 publications

(73 reference statements)

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“…Maf family members also frequently cooperate with members of other transcription factor families (Ho et al, 1996,Huang et al, 2002,Rajaram and Kerppola, 2004,Sevinsky et al, 2004,Aramata et al, 2005 and can also interact with transcriptional coactivators, such as CREB-binding protein and p300 to activate gene transcription (Chen et al, 2002). In our hands co-transfection of c-Maf with either Ets-2 or c-Jun expression plasmids did not show synergistic effects between these transcription factors on the CD13 proximal promoter (data not shown).…”

Section: Discussionmentioning

confidence: 53%

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Mahoney

Petrović

Schacke

et al. 2007

Gene

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Angiogenic growth factors induce the transcription of the cell surface peptidase CD13/APN in activated endothelial cells of the tumor vasculature. Inhibition of CD13/APN abrogates endothelial invasion and morphogenesis in vitro and tumor growth in vivo suggesting a critical functional role for CD13 in angiogenesis. Experiments to identify the transcription factors responsible for this regulation demonstrated that exogenous expression of the proto-oncogene c-Maf, but not other bZip family members tested, potently activates transcription from a critical regulatory region of the CD13 proximal promoter between −115 and −70 bp which is highly conserved among mammalian species. Using promoter mutation, EMSA and ChIP analyses we established that both endogenous and recombinant c-Maf directly interact with an atypical Maf response element contained within this active promoter region via its basic DNA/leucine zipper domain. However full activity of c-Maf requires the amino-terminal transactivation domain, and site-directed mutation of putative phosphorylation sites within the transactivation domain (serines 15 and 70) shows that these sites behave in a dramatic cell type-specific manner. Therefore, this atypical response element predicts a broader range of c-Maf target genes than previously appreciated and thus impacts its regulation of multiple myeloma as well as endothelial cell function and angiogenesis.

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Section: Discussionmentioning

confidence: 53%

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Mahoney

Petrović

Schacke

et al. 2007

Gene

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“…Mutation of these factors causes cataracts in both mouse models and humans (Glaser et al, 1994;Hanson et al, 1994;Semina et al, 1998;Wigle et al, 1999;Blixt et al, 2000;Brownell et al, 2000;Duncan et al 2000;Ring et al, 2000;Semina et al, 2000Semina et al, , 2001Jamieson et al, 2002;Lyon et al, 2003;Berry et al, 2004;Duncan et al, 2004;Rajaram and Kerpolla, 2004). Most of these transcription factors are downstream of Pax6 in the lens.…”

Section: Resultsmentioning

confidence: 99%

Pax6 is misexpressed in Sox1 null lens fiber cells

Donner

Episkopou

et al. 2007

Gene Expression Patterns

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Sox1 null lens fiber cells fail to elongate and have disrupted expression of gamma crystallin. We have evaluated the expression of Sox1 and Pax6 proteins during critical stages of lens morphogenesis, with particular focus on fiber cell differentiation. While Pax6 and Sox1 are co-expressed during early stages of fiber cell differentiation, Sox1 up-regulation coincides temporally with the down-regulation of Pax6, and these proteins therefore display a striking inverse expression pattern in the lens fiber cell compartment. Furthermore, Pax6 is inappropriately expressed in the fiber cells of Sox1 null mice and the Pax6 target, α5 integrin, is simultaneously misexpressed. Finally, we demonstrate a genetic interaction between Sox1 and Pax6, as Sox1 heterozygosity partially rescues the diameter of Pax6 Sey lenses by increasing the number of cells in the fiber cell compartment.

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“…18,19 Expression of γF-crystallin is evident only later in primary lens fibers 58 as Pax6 serves as an inhibitor of its expression mediated by a functional synergism between Maf and Sox proteins. 31,59 It is also of interest that Pax6 has been established as a repressor of fiber-cell specific chicken βB1-crystallin competing with Maf proteins for the same region of DNA. 15,60 In conclusion, different promoter architecture including mutual positions of Maf and Pax6-binding sites, their number, and their distances provide a number of mechanisms to mediate tissue-specific gene expression in the lens, pancreas, and likely in other tissues, during mammalian development.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific Regulation of the Mouse αA-crystallin Gene in Lens via Recruitment of Pax6 and c-Maf to its Promoter

Yang

Cvekl

2005

Journal of Molecular Biology

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Pax6 is a lineage-restricted DNA-binding transcription factor regulating the formation of mammalian organs including brain, eye and pancreas. Pax6 plays key roles during the initial formation of lens lineage, proliferation of lens progenitor and precursor cells and their terminal differentiation. In addition to Pax6, lens fiber cell differentiation is regulated by c-Maf, Prox1 and Sox1. Crystallins are essential lens structural proteins required for light refraction and transparency. Mouse αA-crystallin represents about 17% of all crystallins at the protein level and ranks as one of the most abundant tissue-specific proteins. Lens-specific expression of this gene is regulated at the level of transcription. A promoter fragment of −88 to +46 is capable of driving lens-specific expression in transgenic mouse. Here we provide data suggesting that this lens-specific promoter fragment is comprised of multiple Pax6 and Maf-binding sites. Site-directed mutagenesis of regions within these sites resulted in partially or completely reduced promoter activities in lens cells. Co-transfections using Pax6 and c-Maf alone revealed moderate and strong activations of this promoter, respectively. In contrast to synergistic activation of αB-crystallin by Pax6 and c-Maf, Pax6 has a neutral effect on c-Maf-mediated αA-crystallin promoter activation. Chromatin immunoprecipitations established in vivo interactions of Pax6 and c-Maf with the αA-crystallin promoter in lens cells. Collectively, the present data support a molecular model in which tissue-specific expression of αA-crystallin is regulated by recruitment of Pax6 and c-Maf, two proteins regulating multiple processes of lens differentiation, to its promoter. In addition, the data suggest a molecular model of temporal and spatial regulation of αB, αA and γ-crystallin genes in mouse embryonic lens by using variants of the Pax6/ Maf regulatory module.

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Synergistic Transcription Activation by Maf and Sox and Their Subnuclear Localization Are Disrupted by a Mutation in Maf That Causes Cataract

Cited by 49 publications

References 52 publications

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Pax6 is misexpressed in Sox1 null lens fiber cells

Tissue-specific Regulation of the Mouse αA-crystallin Gene in Lens via Recruitment of Pax6 and c-Maf to its Promoter

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