The Far Upstream Element-binding Proteins Comprise an Ancient Family of Single-strand DNA-binding Transactivators

Davis-Smyth, Terri; Duncan, Robert C.; Zheng, Tian; Michelotti, Gregory A.; Levens, David

doi:10.1074/jbc.271.49.31679

Cited by 161 publications

(153 citation statements)

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“…11e13 FBP (encoded by FUBP1) is the oldest member of a mammalian three gene family of single-strand nucleic acid binding proteins that includes FBP2 encoded by KHSRP and FBP3 encoded by FUBP3. 14 The FBPs are reported to interact with a wide range of DNA or RNA targets and to participate in a variety of biological processes, including transcription, splicing, RNA transport, translational regulation, and mRNA degradation. 15e21 The architecture of the FBPs include a central domain that comprises four regularly spaced K homology (KH) motifs that recognize sequences in single-stranded DNA or RNA with roughly equal (nanomolar) avidity.…”

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“…7,24 FBP, FBP2, and FBP3 have three, four, and two tyrosine-rich motifs, respectively. 14,24 The amino termini of FBP and FBP2 include an a-helix that interacts with RNA recognition motif 2 domain of FIR, 2,4,7,16,23 whereas an A/V substitution in FBP3 precludes this interaction. 16 A variety of in vitro and tissue culture experiments have associated FBP binding with a complex set of DNA and RNA targets.…”

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Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

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The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1 À/À ) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pale livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1 À/À hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1 À/À hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1 À/À embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression. The transcription factor Myc plays a decisive role in cell growth, differentiation, and senescence and so must be highly regulated. The far upstream element (FUSE) binding protein (FBP) binds single-stranded DNA of FUSE 1.7 kb upstream of the major P2 promoter of the human MYC gene. 1e3 FUSE melting in response to dynamic supercoils propagated from the MYC promoters enables FBP binding. FBP activates TFIIH helicase activity to accelerate the transcription cycle from preinitiation complex assembly through promoter escape and onto pause release. 4e6 Positive regulation of MYC is at least in part counteracted by FBP interacting repressor (FIR) that binds FBP and FUSE and opposes TFIIH helicase activity, retarding the transcription cycle. 5,7 Besides MYC, FBP regulates the expression of the cyclin-dependent kinase inhibitor p21, stathmin, and USP29, a powerful stabilizer of p53 induced by oxidative stress. 8e10 Because the FBP/FIR system reads single-stranded DNA sequences exposed by transcriptionally generated dynamic supercoiling, it is proposed that the FBP/ FIR/FUSE system serves as a molecular cruise control that monitors the mechanical output of promoters in real time while providing both positive and negative feedback. 11e13Supported by the NIH

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Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

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“…There is growing evidence that a small subclass of sequenceand/or conformation-specific single-stranded DNA-binding transcription factors may utilize such structures as recognition sites to regulate gene expression (25)(26)(27)(33)(34)(35). Moreover, in the specific case of the human c-MYC gene, DNA in the vicinity of cis-element binding sites for the SSB transactivators, FUSEbinding protein and hnRNPK has been shown to exist in a configuration that is hypersensitive to cleavage by singlestrand-selective agents (51).…”

Section: Fig 2 Tgf-␤1 Specifically Induces Endogenous Vsm ␣-Actin Gmentioning

confidence: 99%

“…Such in vitro evidence of non-B DNA structures with regions of unpairing suggests the potential for such structures in vivo. Whereas the prevailing intracellular temperature, pH, and ionic strength would seem to preclude stable DNA unpairing, there is growing evidence that a small subclass of sequenceand/or conformation-specific, single-stranded DNA-binding transcription factors may utilize such structures as recognition sites in modulating gene expression (25)(26)(27)(33)(34)(35).…”

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Altered Sensitivity to Single-strand-specific Reagents Associated with the Genomic Vascular Smooth Muscle α-Actin Promoter during Myofibroblast Differentiation

Becker

Kelm

Vrana³

et al. 2000

Journal of Biological Chemistry

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Stimulation of quiescent AKR-2B mouse fibroblasts with transforming growth factor ␤1 results in uniform conversion to a myofibroblast-like phenotype as judged by a rapid accumulation of smooth muscle ␣-actin mRNA and protein. Because transcriptional regulation of the smooth muscle ␣-actin gene in these cells might be mediated by single-stranded DNA-binding proteins, we have examined the sensitivity of genomic DNA to chemical reagents with specificity for unpaired bases in a region of the promoter previously implicated in Pur␣, Pur␤, and MSY1 binding in vitro (Kelm, R. J., Jr., Cogan, J. G., Elder, P. K., Strauch, A. R., and Getz, M. J. (1999) J. Biol. Chem. 274, 14238 -14245). Our data reveal specific differences between purified DNA treated in vitro and nucleoprotein complexes treated in living cells. Although some differences were observed in quiescent cells, treatment with transforming growth factor ␤1 resulted in the development of additional sensitivity within 1 h. This enhancement was most pronounced in bases immediately upstream of an MCAT enhancer element-containing polypurine-polypyrimidine tract. A TATA-proximal element of similar base distribution showed no such hyperreactivities. These results suggest that activation of the endogenous smooth muscle ␣-actin gene during myofibroblast conversion is accompanied by specific structural changes in the promoter that are consistent with a decline in single-stranded DNA repressor protein binding.Although many studies have focused on malignant cells themselves, there is an emerging appreciation of the essential role played by stromal components in regulating tumor growth and progression (1). In the stroma of invasive breast cancer for example, myofibroblasts are the most abundant cell type (2), and their persistence has been linked to stromal modifications believed to facilitate tumor cell invasion and metastasis (3, 4). Myofibroblasts, which exhibit morphological and biochemical features intermediately between fibroblasts and smooth muscle cells, were originally identified in granulation tissue (5) where they appear transiently during wound healing and are thought to provide the contractile force necessary for wound closure (6 -9). Because vascular smooth muscle (VSM) 1 ␣-actin gene expression is generally considered the hallmark of the myofibroblast phenotype (10), elucidation of the molecular mechanisms that control VSM ␣-actin gene expression during fibroblast to myofibroblast conversion will likely provide greater insight into the role of this distinctive cell type in cancer progression and wound healing. Unfortunately, convenient in vitro model systems of myofibroblast cytodifferentiation are lacking due to the manifest heterogeneity of VSM ␣-actin expression in many established fibroblastic cells lines (11).Some of our recent studies have focused on identifying the operative cis-acting elements and DNA-binding proteins that regulate mouse VSM ␣-actin promoter activation and repression in serum-stimulated AKR-2B fibroblasts (12-18), a nontransformed clona...

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“…One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (4). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref.…”

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Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Dhamija

Kuehne

Winzen

et al. 2011

Journal of Biological Chemistry

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Inflammatory gene expression is controlled by post-transcriptional mechanisms. Many relevant transcripts contain AU-rich elements (AREs) 4 that can impose rapid degradation and restrict translation (1-3). Several proteins that interact with and mediate the effects of AREs have been identified. One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (4). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref. 5). Most recently it has been found to contribute to regulation of RNA 3Ј-end processing (6).KSRP has been shown to facilitate mRNA degradation by directly binding to AREs and recruiting mRNA-degrading enzymes (7,8). Ksrp Ϫ/Ϫ cells and mice produce more type I interferons as a result of decreased mRNA decay and are refractory to viral infection (9). Different conditions of cellular activation or differentiation have been described to reduce KSRP binding and increase stability of specific mRNAs (e.g. Refs. 10 -13). The proinflammatory cytokine IL-1 can induce stabilization of KSRP target mRNAs, including that of IL-6 (14, 15), by reducing interaction of KSRP with the ARE presumably as a result of KSRP phosphorylation by p38 MAP kinase (10).IL-6, originally cloned as 26-kDa protein (16), IFN-␤2 (17), and BSF-2 (18), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (19,20). IL-6 is induced in various cell types by a plethora of activators. Among the strongest and first identified are the proinflammatory cytokines tumor necrosis factor (TNF) (21) and IL-1 (22). Expression of IL-6 is controlled by transcriptional and post-transcriptional mechanisms. The latter involve AREs and a putative stem-loop structure that cause rapid degradation of the mRNA (23). Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of . We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP. Interaction of KSRP with the IL-6 ARE is direct and is decreased in response to IL-1, suggesting a novel, miRNA-independent function for KSRP in translation.

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The Far Upstream Element-binding Proteins Comprise an Ancient Family of Single-strand DNA-binding Transactivators

Cited by 161 publications

References 37 publications

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Altered Sensitivity to Single-strand-specific Reagents Associated with the Genomic Vascular Smooth Muscle α-Actin Promoter during Myofibroblast Differentiation

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

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