Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development

Kim, J. I.; Li, Tiansen; Ho, I‐Cheng; Grusby, Michael J.; Glimcher, Laurie H.

doi:10.1073/pnas.96.7.3781

Cited by 222 publications

(179 citation statements)

References 40 publications

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“…Not only does c-Maf likely function at low concentrations but the c-Maf protein may be quite stable and relatively refractory to siRNA effects. c-Maf null mice have been produced and found to die in utero between embryonic day 15.5 and 18.5 (Kim et al, 1999), precluding the analysis of CD13 expression in pathologic angiogenesis models. The cause of the premature death in the c-Maf null mouse has not been determined, but the relatively late stage mortality indicates that c-Maf is either compensated for by another large Maf or not involved in embryonic vasculogenesis.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…GAD65, EGAD, and GABA were initially detected in the lens placode, which is the site of expression of multiple transcription factors known as regulators of lens induction and fiber cell differentiation, such as Pax6, Six3, Eya, Dach1, Mafs, Sox2, Sox3, and Prox1 (Kawauchi et al, 1999;Kim et al, 1999;Wigle et al, 1999;Ogino and Yasuda, 2000;Ring et al, 2000;Duncan et al, 2002Duncan et al, , 2004Cui et al, 2004;Purcell et al, 2005). Pax6, Sox, c-Maf, and Prox1 have consensus binding sites in conserved regions of GAD65 and GAD67 genes (F. Erdélyi and Z.D.…”

Section: Transcriptional Regulation Of Gad In the Lens: Involvement Omentioning

confidence: 99%

“…c-Maf is a basic domain/leucine zipper domain protein, member of the Maf family of transcription factors, which play a major role in ocular development (Reza et al, 2002;Reza and Yasuda, 2004). The absence of either c-Maf or Prox1 results in a strikingly similar phenotype: disrupted lens elongation and synthesis of crystallins due to failure to withdraw from the cell cycle at the initial stages of fiber cell differentiation (Kawauchi et al, 1999;Kim et al, 1999;Wigle et al, 1999;Ring et al, 2000;Lavado and Oliver, 2007). It is not known at present whether Prox1 and/or c-Maf directly regulate GAD genes in the lens.…”

Section: Transcriptional Regulation Of Gad In the Lens: Involvement Omentioning

confidence: 99%

GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5

Kwakowsky

Schwirtlich

Zhang

et al. 2007

Developmental Dynamics

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Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the adult nervous system and its biosynthetic enzyme glutamic acid decarboxylase (GAD) are abundantly expressed in the embryonic nervous system and are involved in the modulation of cell proliferation, migration, and differentiation. Here we describe for the first time the expression of GABA and embryonic and adult GAD isoforms in the developing mouse lens. We show that the GAD isoforms are sequentially induced with specific spatiotemporal profiles: GAD65 and embryonic GAD isoforms prevail in primary fibers, while GAD67 is the predominant GAD expressed in the postnatal secondary fibers. This pattern correlates well with the expression of Dlx2 and Dlx5, known as upstream regulators of GAD. GABA and GAD are most abundant at the tips of elongating fibers and are absent from organelle-free cells, suggesting their involvement is primarily in shaping of the cytoskeleton during fiber elongation stages. Developmental Dynamics 236: 3532-3544, 2007.

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“…Similarly, simultaneous mutations of both Maf-binding elements in Xenopus ␤B1-crystallin result in inactivation of the promoter (Mizuno et al, 2005). In addition, differentiation of the lens is blocked in Maf-gene knockout mice, and the expression of most ␣-and ␤-crystallins is almost abolished (Kim et al, 1999;Ring et al, 2000), providing alternative evidence that Maf protein functions as a key regulator in these gene families.…”

Section: Discussionmentioning

confidence: 99%

Recapitulation of human βB1‐crystallin promoter activity in transgenic zebrafish

Hou

Kuo

Luo

et al. 2005

Developmental Dynamics

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Development of the eye is morphologically similar among vertebrates, indicating that the underlying mechanism regulating the process may have been highly conserved during evolution. Herein we analyzed the promoter of the human ␤B1-crytallin gene in zebrafish by transgenic experiments. To delineate the evolutionarily conserved regulatory elements, we performed serial deletion assays in the promoter region. The results demonstrated that the ؊90/؉61-bp upstream proximal promoter region is sufficient to confer lens-tissue specificity to the human ␤B1-crystallin gene in transgenic zebrafish. Through phylogenetic sequence comparisons and an electrophoretic mobility shift assay (EMSA), a highly conserved cis-element of a six-base pair sequence TG(A/C)TGA, the consensus sequence for the Maf protein binding site, within the proximal promoter region was revealed. Further, a site-mutational assay showed that this element is crucial for promoter activity. These data suggest that the fundamental transcriptional regulatory mechanism of the ␤B1-crystallin gene has been well conserved between humans and zebrafish, and plausibly among all vertebrates, during evolution. Developmental Dynamics 235:435-443, 2006.

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Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development

Abstract: The

Cited by 222 publications

References 40 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

GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5

Recapitulation of human βB1‐crystallin promoter activity in transgenic zebrafish

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