The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light-chain 2 gene via independent cis regulatory elements.

Navankasattusas, Sutip; Sawadogo, Michèle; Bilsen, Marc van; Dang, Chi V.; Chien, Kenneth R.

doi:10.1128/mcb.14.11.7331

Cited by 74 publications

(39 citation statements)

References 59 publications

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“…At least two protein binding sites are important. The HFla site has been reported to bind two ubiquitous proteins, USF (Navankasattusas et al, 1994) and the Y-box protein EFRA/YB-1 (Zhou and Chien, 1995). The HFlb site can bind MEF2/RSRF proteins Navankasattusas et al, 1992) but also a novel, tissue-restricted zinc finger protein (Zhu et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…It is thought that gene expression from this DNA element is regulated by controlling the binding of these various proteins. In particular, binding of USF to the HFla sequence may inhibit expression (Navankasattusas et al, 1994) whereas YB-1 binding may stimulate expression (Zhou and Chien, 1995). It will be interesting to determine whether activation of MKK and ERK activity affects the biological functions of these or other transcription factors at this site.…”

Section: Discussionmentioning

confidence: 99%

“…Several sequence elements that are important in conferring cardiac specificity and induction have been identified (Zhu et al, , 1993Navankasattusas et al, 1992Navankasattusas et al, , 1994Lee et al, 1994). These include a negative regulatory sequence (HF3) that seems to prevent noncardiac expression (Lee et al, 1994), an E box (MLE) that binds the helix-loop-helix transcription factor USF (Navankasattusas et al, 1994), and a sequence (HF1) that is sufficient and required for cardiac-specific expression Lee et al, 1994 1993 ;Navankasattusas et al, 1992;Zhou and Chien, 1995). To screen for possible target sequences that could mediate inhibition of the MLC-2 promoter by active MKK, we performed transient transfection experiments with mutated versions of the 250-bp promoter containing inactivating point mutations in each of these various DNA elements Navankasattusas et al, 1992).…”

Section: Inhibition By Active Mkk Of the Mlc-2 Promotermentioning

confidence: 99%

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Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Thorburn

Carlson

Mansour

et al. 1995

MBoC

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Signaling via the Ras pathway involves sequential activation of Ras, Raf-1, mitogenactivated protein kinase kinase (MKK), and the extracellular signal-regulated (ERK) group of mitogen-activated protein (MAP) kinases. Expression from the c-Fos, atrial natriuretic factor (ANF), and myosin light chain-2 (MLC-2) promoters during phenylephrine-induced cardiac muscle cell hypertrophy requires activation of this pathway. Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters. In this study, we tested whether constitutively active MKK, the molecule immediately downstream of Raf, was sufficient to induce expression. Expression of constitutively active MKK induced ERK2 kinase activity and caused expression from the c-Fos promoter, but did not significantly activate expression of reporter genes under the control of either the ANF or MLC-2 promoters. Expression of CL100, a phosphatase that inactivates ERKs, prevented expression from all of the promoters. Taken together, these data suggest that ERK activation is required for expression from the Fos, ANF, and MLC-2 promoters but MKK and ERK activation is sufficient for expression only from the Fos promoter. Constitutively active MKK synergized with phenylephrine to increase expression from a c-Fos-or an APi-driven reporter. However, active MKK inhibited phenylephrine-and Raf-1-induced expression from the ANF and MLC-2 promoters. A DNA sequence in the MLC-2 promoter that is a target for inhibition by active MKK, but not CL100, was mapped to a previously characterized DNA element (HF1) that is responsible for cardiac specificity. Thus, activation of cardiac gene expression during phenylephrine-induced hypertrophy requires ERK activation but constitutive activation by MKK can inhibit expression by targeting a DNA element that controls the cardiac specificity of gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Inhibition By Active Mkk Of the Mlc-2 Promotermentioning

confidence: 99%

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Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Thorburn

Carlson

Mansour

et al. 1995

MBoC

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“…For example, the insulin gene has been proposed to be controlled by the combinatorial actions of E47 HLH proteins and cell-specific homeodomain proteins (22,23). The USF HLH proteins have also been shown to functionally interact with other DNA binding proteins to activate transcription, including in a cell-specific manner (32,33,38). In the case of the CT/CGRP enhancer, we propose that cell specificity is provided by the OB2 protein.…”

Section: Activity Of the Ct/cgrp Enhancer In The Context Of Flanking mentioning

confidence: 99%

Binding of Upstream Stimulatory Factor and a Cell-specific Activator to the Calcitonin/Calcitonin Gene-related Peptide Enhancer

Lanigan

Russo

1997

Journal of Biological Chemistry

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The calcitonin/calcitonin gene-related peptide (CT/ CGRP) gene is selectively transcribed in thyroid C cells and neurons. We have previously shown that the rat CT/CGRP cell-specific enhancer is synergistically regulated by a helix-loop-helix (HLH) protein and the OB2 octamer-binding protein. In this report, we show that the HLH-OB2 enhancer is required for full promoter activity, even in the context of other HLH elements.Since this enhancer appears to be a major controlling element, we have characterized the HLH and OB2 DNA binding proteins. We have identified the major HLH complex as a heterodimer of the ubiquitous upstream stimulatory factor (USF)-1 and USF-2 proteins. USF bound the enhancer with a reasonably high affinity (K D 1.6 nM), comparable to other genes. Characterization of a series of mutations revealed that a portion of the HLH motif is also recognized by OB2 and confirmed that HLH activity requires OB2. We have shown that OB2 is a single DNA binding protein based on UV cross-linking studies. The 68-kDa protein-DNA complex was detected only in C cell lines, including a human C cell line that has robust HLH-OB2 enhancer activity. These results suggest that the calcitonin/CGRP gene is controlled by the combinatorial activity of a ubiquitous USF HLH heterodimer and an associated cell-specific activator.

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“…The ubiquitously expressed factor USF commonly consists of two subunits, USF-1 and USF-2 (26), and has been shown to be a transcriptional activator in combination with other factors (27)(28)(29)(30). For example, in the immunoglobulin heavy chain enhancer, activity is detected only in the presence of a three protein-DNA complex consisting of USF, PU.1, and Ets-1 (15).…”

Section: Discussionmentioning

confidence: 99%

B Cell-specific Activator Protein Prevents Two Activator Factors from Binding to the Immunoglobulin J ChainPromoter until the Antigen-driven Stages of B Cell Development

Wallin¹,

Rinkenberger²,

Rao³

et al. 1999

Journal of Biological Chemistry

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The immunoglobulin J chain gene is inducibly transcribed in mature B cells upon antigen recognition and a signal from interleukin-2 (IL-2). B cell-specific activator protein (BSAP), a transcription factor that silences J chain transcription, has been identified as a nuclear target of the IL-2 signal. The levels of BSAP progressively decrease in response to IL-2 and this change correlates with the differentiation of B cells into antibody secreting plasma cells. Here we report the binding of the upstream stimulatory factor (USF) to an E-box motif immediately upstream from the BSAP site on the J chain promoter. Mutations in the USF binding motif significantly decrease J chain promoter activity in J chain expressing B cell lines. We also show that a functional relationship exists between USF and a second J chain positive-regulating factor, B-MEF2, using co-immunoprecipitation assays and transfections. Finally, we provide evidence that the binding of BSAP prevents USF and B-MEF2 from interacting with the J chain promoter during the antigen-independent stages of B cell development. It is not until the levels of BSAP decrease during the antigen-driven stages of B cell development that both USF and B-MEF2 are able to bind to their respective promoter elements and activate J chain transcription.During a primary immune response to foreign antigens, mature B cells become activated and differentiate into pentamer IgM-secreting plasma cells. One of the critical events in this process is the synthesis of the immunoglobulin J chain protein required for the assembly and secretion of pentamer IgM antibody (1). Studies of both normal B cells and model B cell lines have shown that J chain synthesis is tightly regulated at the transcriptional level. For efficient J chain transcription to occur, activation signals from both the B cell receptor and the interleukin-2 (IL-2) 1 or IL-5 receptors are needed. Correlating with IL-2/IL-5 induced gene transcription is the appearance of a DNase I-hypersensitive site (bp Ϫ170 to ϩ88) on the J chain promoter of activated B cells (2, 3). The full activity of the J chain promoter is contained within this hypersensitive region, as has been shown using 5Ј deletion mutants in a CAT reporter system (4).Three regulatory elements have been found to be present within this region. These include a T-rich positive regulatory element denoted JA (Ϫ74 to Ϫ60), a purine-rich sequence (Ϫ58 to Ϫ47) denoted JB, and a repressive motif, JC (Ϫ127 to Ϫ110) (5-7). The factor interacting with the JA sequence has recently been identified to be a member of the myocyte enhancer factor-2 (MEF-2) family that is expressed in the B cell lineage, denoted B-MEF2 (5). The JB element has previously been shown to interact with transcription factor PU.1, a member of the Ets family of transcription factors expressed in hematopoietic lineages including monocytes, macrophages, and B lymphoid cells (6). Mutational analyses in J chain positive cell lines have indicated positive regulatory roles for both PU.1 and B-MEF2; base changes tha...

show abstract

The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light-chain 2 gene via independent cis regulatory elements.

Cited by 74 publications

References 59 publications

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Binding of Upstream Stimulatory Factor and a Cell-specific Activator to the Calcitonin/Calcitonin Gene-related Peptide Enhancer

B Cell-specific Activator Protein Prevents Two Activator Factors from Binding to the Immunoglobulin J ChainPromoter until the Antigen-driven Stages of B Cell Development

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