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Results for “transcription factor evolution”

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PubMed1993

Zebra fish myc family and max genes: differential expression and oncogenic activity throughout vertebrate evolution.

To gain insight into the role of Myc family oncoproteins and their associated protein Max in vertebrate growth and development, we sought to identify homologs in the zebra fish (Brachydanio rerio). A combination of a polymerase chain reaction-based cloning strategy and low-stringency hybridization screening allowed for the isolation of zebra fish c-, N-, and L-myc and max genes; subsequent structural characterization showed a high degree of conservation in regions that encode motifs of known functional significance. On the functional level, zebra fish Max, like its mammalian counterpart, served to suppress the transformation activity of mouse c-Myc in rat embryo fibroblasts. In addition, the zebra fish c-myc gene proved capable of cooperating with an activated H-ras to effect the malignant transformation of mammalian cells, albeit with diminished potency compared with mouse c-myc. With respect to their roles in normal developing tissues, the differential temporal and spatial patterns of steady-state mRNA expression observed for each zebra fish myc family member suggest unique functions for L-myc in early embryogenesis, for N-myc in establishment and growth of early organ systems, and for c-myc in increasingly differentiated tissues. Furthermore, significant alterations in the steady-state expression of zebra fish myc family genes concomitant with relatively constant max expression support the emerging model of regulation of Myc function in cellular growth and differentiation.

Amino Acid Sequence↗
PubMed2000

Regulation of the mammalian alcohol dehydrogenase genes.

This review focuses on the regulation of the mammalian medium-chain alcohol dehydrogenase (ADH) genes. This family of genes encodes enzymes involved in the reversible oxidation of alcohols to aldehydes. Interest in these enzymes is increased because of their role in the metabolism of beverage alcohol as well as retinol, and their influence on the risk for alcoholism. There are six known classes ADH genes that evolved from a common ancestor. ADH genes differ in their patterns of expression: most are expressed in overlapping tissue-specific patterns, but class III ADH genes are expressed ubiquitously. All have proximal promoters with multiple cis-acting elements. These elements, and the transcription factors that can interact with them, are being defined. Subtle differences in sequence can affect affinity for these factors, and thereby influence the expression of the genes. This provides an interesting system in which to examine the evolution of tissue specificity. Among transcription factors that are important in multiple members of this gene family are the C/EBPs, Sp1,USF, and AP1, HNF-1, CTF/NF-1, glucocorticoid, and retinoic acid receptors, and several as-yet unidentified negative elements, are important in at least one of the genes. There is evidence that cis-acting elements located far from the proximal promoter are necessary for proper expression. Three of the genes have upstream AUGs in the 5' nontranslated regions of their mRNA, unusual for mammalian genes. The upstream AUGs have been shown to significantly affect expression of the human ADH5 gene.

Alcohol Dehydrogenase↗
PubMed1995

c-Myc and Max transregulate the mouse ornithine decarboxylase promoter through interaction with two downstream CACGTG motifs.

Ornithine decarboxylase (ODC), the first enzyme in the biosynthesis of polyamines, is essential for the process of cellular proliferation. ODC is a typical delayed early gene, as its mitogenic activation requires ongoing protein synthesis in the stimulated cells. This study provides evidence that the immediate early c-Myc protein is a potential transactivator of the ODC gene. We demonstrate that overexpression of c-Myc results in efficient activation of the ODC promoter, whereas overexpression of Max exerts a repressive effect. Both effects depend on the presence of two evolutionary conserved CACGTG motifs found in the first intron of the ODC gene. Transactivation of the ODC promoter also requires the dimerization of c-Myc with Max. Interestingly, over-expression of USF, a member of the same family of proteins which efficiently binds these two CACGTG motifs, fails to transregulate the ODC promoter. Our data suggest that c-Myc and Max are potential transcriptional regulators of the ODC promoter.

Animals↗
PubMed2026

GATA2 deficiency: enhancer deregulation, immune surveillance failure, and clonal evolution.

Germline mutations in GATA2 cause a syndromic inborn error of immunity characterized by cytopenia, infections, immune dysregulation, and a marked predisposition to myelodysplastic syndrome and acute myeloid leukemia. Initially defined by the DCML phenotype-dendritic cell, monocyte, B- and NK-cell deficiency-GATA2 deficiency is now recognized as a disorder of global immune-hematopoietic homeostasis. Recent multi-omics and experimental models reveal enhancer-driven inflammatory rewiring, IRF8-dependent lineage imbalance, and premature hematopoietic aging. In parallel, adaptive immune defects, including impaired B- and T-cell development and function, contribute to defective immune surveillance. These alterations not only explain susceptibility to infection but also shape clonal evolution and malignant transformation. Clinically, improved risk stratification and transplant outcomes underscore the importance of early recognition and monitoring of immune dysfunction. GATA2 deficiency thus represents a paradigm linking immune dysregulation, inflammatory stress, and cancer predisposition.

Humans↗
PubMed1999

Activity regulation of Hox proteins, a mechanism for altering functional specificity in development and evolution.

The closely related Hox transcription factors Ultrabithorax (Ubx) and Antennapedia (Antp) respectively direct first abdominal (A1) and second thoracic (T2) segment identities in Drosophila. It has been proposed that their functional differences derive from their differential occupancy of DNA target sites. Here we show that a hybrid version of Ubx (Ubx-VP16), which possesses an enhanced transcriptional activation function, no longer directs A1 denticle pattern in embryonic epidermal cells. Instead, it mimics Antp in directing T2 denticle pattern, and it can rescue the cuticular loss-of-function phenotype of Antp mutants. In cells that do not produce denticles, Ubx-VP16 appears to have largely retained its normal repressive regulatory functions. These results suggest that the modulation of Hox activation and repression functions can account for segment-specific morphological differences that are controlled by different members of the Hox family. Our results also are consistent with the idea that activity regulation underlies the phenotypic suppression phenomenon in which a more posterior Hox protein suppresses the function of a more anterior member of the Hox cluster. The acquisition of novel activation and repression potentials in Hox proteins may be an important mechanism underlying the generation of subtle morphological differences during evolution.

Animals↗
PubMed1998

Evolution of a mammalian promoter through changes in patterns of transcription factor binding.

Previously, we identified evolutionarily derived changes in the pattern of nuclear factor binding to overlapping sites (termed A, B, and C, in proximal to distal order) within the promoter region of the murine D7Rp2e gene. In Mus domesticus, strong binding occurs at site B, with weak binding at sites A and C; in M. pahari, strong binding is observed at sites A and C, with weak binding at site B. The M. pahari-specific occupancy pattern is associated with repression of transcription. Presently, we have identified two interspecies changes, a single A --> G substitution within site B and a 7-bp indel within site C, that are primary determinants of the interspecies differences. These mutations alter both the pattern of binding site occupancy and the ability to repress transcription. The results are discussed in terms of a model involving a dynamic equilibrium between states of binding site occupancy, the nature of which can be modified during evolution.

Animals↗
PubMed2006

Cross-species annotation of basic leucine zipper factor interactions: Insight into the evolution of closed interaction networks.

Dimeric basic leucine zipper (bZIP) factors constitute one of the most important classes of enhancer-type transcription factors. In vertebrates, bZIP factors are involved in many cellular processes, including cell survival, learning and memory, cancer progression, lipid metabolism, and a variety of developmental processes. These factors have the ability to homodimerize and heterodimerize in a specific and predictable manner, resulting in hundreds of dimers with unique effects on transcription. In recent years, several studies have described dimerization preferences for bZIP factors from different species, including Homo sapiens, Drosophila melanogaster, Arabidopsis thaliana, and Saccharomyces cerevisiae. Here, these findings are summarized as novel, graphical representations of closed, interacting protein networks. These representations combine phylogenetic information, DNA-binding properties, and dimerization preference. Beyond summarizing bZIP dimerization preferences within selected species, we have included annotation for a solitary bZIP factor found in the primitive eukaryote, Giardia lamblia, a possible evolutionary precursor to the complex networks of bZIP factors encoded by other genomes. Finally, we discuss the fundamental similarities and differences between dimerization networks within the context of bZIP factor evolution.

Amino Acid Sequence↗
PubMed2003

Follicle-stimulating hormone promotes nuclear exclusion of the forkhead transcription factor FoxO1a via phosphatidylinositol 3-kinase in porcine granulosa cells.

The forkhead family of transcription factors is conserved in evolution and known to play critical roles in the regulation of cellular differentiation and proliferation in many systems. The current studies demonstrate for the first time that forkhead homolog in rhabdomyosarcoma (FKHR) (FoxO1a) is expressed in porcine granulosa cells, and FSH stimulates FKHR phosphorylation and regulates its subcellular localization in this system. RT-PCR and Western blot studies demonstrated that FKHR is expressed and showed no change in FKHR message or protein levels in response to FSH (0-6 h). However, [32p]-orthophosphate labeling of cultured granulosa cells revealed robust phosphorylation after FSH treatment for 30 min. In addition, FSH caused nuclear exclusion of FKHR in these cells, apparently through the phosphatidylinositol 3-kinase signal transduction pathway. The cytosolic accumulation of FKHR protein that was observed in FSH-treated cells both by Western blot and immunohistochemistry was blocked when the cells were preincubated with the phosphatidylinositol 3-kinase inhibitor LY294002. Our data also demonstrate that Akt/protein kinase B, an established kinase for FKHR, is phosphorylated in response to FSH treatment. Interestingly, although FKHR was phosphorylated by 30 min after FSH treatment, the time course for Akt phosphorylation was relatively delayed and sustained. Although these studies do not preclude Akt involvement in FSH-stimulated FKHR phosphorylation, they do suggest that other kinases may contribute to rapid signaling to FKHR. Because FKHR has been shown to activate genes involved in apoptosis and growth inhibition, FSH may promote growth and survival by initiating the phosphorylation of FKHR, causing its nuclear exclusion, and reducing its effect as a cell cycle arrest or death-promoting transcription factor.

Animals↗
PubMed1994

Transcription factors modulating angiotensinogen gene expression in hepatocytes.

The gene encoding angiotensinogen is regulated at the transcriptional level in hepatocytes in response to glucocorticoids and inflammatory cytokines (IL-1 and TNF). These hormones activate transcription of the angiotensinogen gene by changing the abundance of DNA binding proteins that interact with a multihormone-inducible enhancer located between nucleotides -615 to -440 upstream of the major transcription start site. Activation of this enhancer in hepatocytes is effected by glucocorticoid- and cytokine-inducible DNA binding proteins. Cytokine induction is mediated through the interaction of two classes of transcription factors that bind to the acute-phase response element (APRE): nuclear factor-kappa B (NF-kappa B), and CCAAT-Box/Enhancer Binding Protein (C/EBP). NF-kappa B is a multiprotein DNA binding complex sequestered in the cytoplasm that is induced in the nucleus by cytokines, whereas C/EBP is a nuclear transcription factor family implicated in the expression of differentiated hepatic proteins. During the acute-phase response, individual C/EBP family members are discordinately regulated: C/EBP alpha levels fall, whereas another C/EBP family member termed nuclear factor IL6 (NF-IL6), is induced. We investigated the interaction between the two acute-phase induced APRE-binding proteins: NF-kappa B and NF-IL6. Both proteins bind to overlapping nucleotides in a mutually exclusive fashion with similar affinities for the APRE. NF-IL6, a less potent transactivator, attenuates NF-kappa B mediated transcription late in the evolution of the acute-phase response. These observations argue for a temporal model of sequentially-expressed transcription factors occupying the APRE during the evolution of the inflammatory process.

Acute-Phase Reaction↗
PubMed1998

Conservation and divergence of NF-Y transcriptional activation function.

The CCAAT-binding protein NF-Y is involved in the regulation of a variety of eukaryotic genes and is formed in higher eukaryotes by three subunits NF-YA/B/C. We have characterized NF-Y of the trematode parasite Schistosoma mansoni and studied the structure and the function of the SMNF-YA subunit. In this work, we present the cloning and sequence analysis of the B subunit of the parasite factor. SMNF-YB contains the conserved HAP-3 homology domain but the remaining part of the protein was found to be highly divergent from all other species. We demonstrated by transfections of GAL4 fusion constructs, that mouse NF-YB does not contain activation domains while the C-terminal part of SMNF-YB has transcriptional activation potential. On the other hand, the N-terminal parts of SMNF-YA and mouse NF-YA were shown to mediate transactivation; the integrity of a large 160 amino acid glutamine-rich domain of NF-YA was required for this function and an adjacent serine- and threonine-rich domain was necessary for full activity in HepG2, but redundant in other cell types. Transactivation domains identified in SMNF-YB are also rich in serine and threonine residues. Our results indicate that serine/threonine-richsequences from helminth parasites potentiate trans-cription and that such structures have diverged during evolution within the same transcription factor.

3T3 Cells↗
PubMed2002

Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA.

Characterization of the basic transcription machinery of mammalian mitochondrial DNA (mtDNA) is of fundamental biological interest and may also lead to therapeutic interventions for human diseases associated with mitochondrial dysfunction. Here we report that mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M) are necessary for basal transcription of mammalian mitochondrial DNA (mtDNA). Human TFB1M and TFB2M are expressed ubiquitously and can each support promoter-specific mtDNA transcription in a pure recombinant in vitro system containing mitochondrial RNA polymerase (POLRMT) and mitochondrial transcription factor A. Both TFB1M and TFB2M interact directly with POLRMT, but TFB2M is at least one order of magnitude more active in promoting transcription than TFB1M. Both factors are highly homologous to bacterial rRNA dimethyltransferases, which suggests that an RNA-modifying enzyme has been recruited during evolution to function as a mitochondrial transcription factor. The presence of two proteins that interact with mammalian POLRMT may allow flexible regulation of mtDNA gene expression in response to the complex physiological demands of mammalian metabolism.

Amino Acid Sequence↗
PubMed2003

The Drm-Bowl-Lin relief-of-repression hierarchy controls fore- and hindgut patterning and morphogenesis.

The elucidation of pathways linking patterning to morphogenesis is a problem of great interest. We show here that, in addition to their roles in patterning and morphogenesis of the hindgut, the Drosophila genes drumstick (drm) and bowl are required in the foregut for spatially localized gene expression and the morphogenetic processes that form the proventriculus. drm and bowl belong to a family of genes encoding C(2)H(2) zinc finger proteins; the other two members of this family are odd-skipped (odd) and sob. In both the fore- and hindgut, drm acts upstream of lines (lin), which encodes a putative transcriptional regulator, and relieves its repressive function. In spite of its phenotypic similarities with drm, bowl was found in both foregut and hindgut to act downstream, rather than upstream, of lin. These results support a hierarchy in which Drm relieves the repressive effect of Lin on Bowl, and Bowl then acts to promote spatially localized expression of genes (particularly the JAK/STAT pathway ligand encoded by upd) that control fore- and hindgut morphogenesis. Since the odd-family and lin are conserved in mosquito, mouse, and humans, we propose that the odd-family genes and lin may also interact to control patterning and morphogenesis in other insects and in vertebrates.

Animals↗
PubMed2006

High regulatory gene use in sea urchin embryogenesis: Implications for bilaterian development and evolution.

A global scan of transcription factor usage in the sea urchin embryo was carried out in the context of the Strongylocentrotus purpuratus genome sequencing project, and results from six individual studies are here considered. Transcript prevalence data were obtained for over 280 regulatory genes encoding sequence-specific transcription factors of every known family, but excluding genes encoding zinc finger proteins. This is a statistically inclusive proxy for the total "regulome" of the sea urchin genome. Close to 80% of the regulome is expressed at significant levels by the late gastrula stage. Most regulatory genes must be used repeatedly for different functions as development progresses. An evolutionary implication is that animal complexity at the stage when the regulome first evolved was far simpler than even the last common bilaterian ancestor, and is thus of deep antiquity.

Animals↗