Structure and function of helix-loop-helix proteins

Murre, Cornelis; Bain, Gretchen; Dijk, Marc A. van; Engel, Isaac; Furnari, Beth; Massari, Mark E.; Matthews, James R.; Quong, Melanie W.; Rivera, Richard; Stuiver, Maarten H.

doi:10.1016/0167-4781(94)90001-9

Cited by 444 publications

(369 citation statements)

References 51 publications

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“…Id3, like other Id proteins, has been shown to interact with bHLH transcription factors, especially the E proteins, which include the E2A gene products E12 and E47, HeLa E-box binding protein and E2-2, and exhibit a wide tissue distribution, regulating the expression of genes containing E box (GANNTC) or N box (CACNAG) sequences (Murre et al, 1994). Of considerable interest and relevance to our study is the observation that ectopic expression of Id3-induced p53-independent apoptosis and suppressed clonogenicity of primary rat embryo fibroblasts, while cotransfection with either Bcl2, BclxL or E47, a bHLH Id3-interacting transcription factor, blocked apoptosis and led to cell immortalization (Norton and Atherton, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…However, while all other HLH classes contain a basic DNA-binding domain at the N-terminus (hence, the designation 'bHLH') and bind consensus E-box (CANNTG), or N box (CACNAG) DNA sequences (Murre et al, 1989b;Murre et al, 1994) found in regulatory regions of many genes involved in growth, differentiation, and apoptosis, the Id proteins lack this basic region, acting as DN inhibitors of class I and II proteins. By sequestering class I proteins and preventing their interaction with class II proteins, Ids can block expression of some tissue and differentiation-specific genes (Norton, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

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Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

et al. 2006

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“…The bHLH protein family of transcription factors is divided into three classes according to their DNA-binding properties, structural features, and tissue distribution (61). Factors of the E2A family (E12, E47, E2-5) are ubiquitously expressed members of class A.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic β-Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein β

Lu¹,

Seufert²,

Habener

1997

Journal of Biological Chemistry

120

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Chronic exposure of ␤-cells to supraphysiologic glucose concentrations results in decreased insulin gene transcription. Here we identify the basic leucine zipper transcription factor, CCAAT/enhancer-binding protein ␤ (C/EBP␤), as a repressor of insulin gene transcription in conditions of supraphysiological glucose levels. C/EBP␤ is expressed in primary rat islets. Moreover, after exposure to high glucose concentrations the ␤-cell lines HIT-T15 and INS-1 express increased levels of C/ EBP␤. The rat insulin I gene promoter contains a consensus binding motif for C/EBP␤ (CEB box) that binds C/EBP␤. In non-␤-cells C/EBP␤ stimulates the activity of the rat insulin I gene promoter through the CEB box. Paradoxically, in ␤-cells C/EBP␤ inhibits transcription, directed by the promoter of the rat insulin I gene by direct protein-protein interaction with a heptad leucine repeat sequence within activation domain 2 of the basic helix-loop-helix transcription factor E47. This interaction leads to the inhibition of both dimerization and DNA binding of E47 to the E-elements of the insulin promoter, thereby reducing functionally the transactivation potential of E47 on insulin gene transcription. We suggest that the induction of C/EBP␤ in pancreatic ␤-cells by chronically elevated glucose levels may contribute to the impaired insulin secretion in severe type II diabetes mellitus.Insulin is a hormone essential for the control of mammalian glucose homeostasis and is produced predominantly in pancreatic ␤-cells of adult animals (1). The expression of the insulin gene occurs to a large extent at the level of transcription. Control elements residing in the 5Ј 350-base pair sequence flanking exon 1 of the rat insulin I gene are sufficient to direct ␤-cell-specific expression (2) (Fig. 1A). Arrays of A and E elements 1 (Far-FLAT, Nir-P1) constitute symmetrical enhansons that cooperatively account for Ͼ90% of the transcriptional activity of the insulin gene promoter (3). The E elements are recognition motifs for transcription factors in the basic helixloop-helix (bHLH) 2 family, such as E12 and E47, which activate the insulin promoter in close synergism with A element binding homeobox transcription factors, such as IDX-1.Chronic hyperglycemia may contribute to the pancreatic ␤-cell dysfunction observed in patients with type II diabetes, a phenomenon attributed to the concept of glucose toxicity (4). Studies using in vivo animal models and in vitro ␤-cell lines have demonstrated that a reduction of insulin gene transcription by glucose toxicity is associated with the loss of transactivator proteins such as IDX-1/IPF-1/STF-1 and RIPE3b1-binding protein (5-10). Because insulin gene transcription is both positively and negatively regulated, we sought to identify repressors that might also mediate the effects of glucose toxicity on insulin gene transcription. In this report we describe CCAAT/enhancer binding protein-␤ (C/EBP␤) as a glucoseinduced repressor of insulin gene transcription.C/EBPs are a family of transcription factors that regulate...

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“…Net, like other members of TCFs, has three similar domains, A, B and C, respectively involved in DNA binding, interaction with SRF and activation of transcription when phosphorylated by MAPKs (Janknecht et al 1993(Janknecht et al , 1994(Janknecht et al , 1995Hill et al 1995;Whitmarsh et al 1995;Treisman 1996). However, Net is different from other TCFs in its ability to repress transcription of c-fos (Giovane et al 1994;Maira et al 1996;Criqui-Filipe et al 1999;Buchwalter et al 2004Buchwalter et al , 2005, which is correlated with it's two autonomous inhibitory domains, the net inhibitory domain (NID) (Murre et al 1994) and the C-terminal binding protein interaction domain (CID). The CID interacts with the corepressor E1A C-terminal binding protein, and then inhibits transcription through regulating histone deacetylase activity (Maira et al 1996).…”

Section: Cell Culturementioning

confidence: 99%

Growth Inhibitory Effect of the Ternary Complex Factor Net on Human Pancreatic Carcinoma Cell Lines

Zhu

et al. 2008

Tohoku J. Exp. Med.

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Pancreatic carcinoma is one of the most aggressive malignancies and carries the most dismal prognoses of all cancers. A better understanding of the genes involving in tumor development may allow us to tackle this rapidly progressive disease. The Net gene belongs to the ternary complex transcription factor (TCF) family and is regulated by the Ras/mitogen-activited protein kinase-signaling pathway. Under basal conditions, Net shows strong represssing function on transcription of proto-oncogene gene c-fos. Moreover, the lower expression of Net has been noted in some carcinoma cells, such as cervical cancer. To study the effect of Net on c-fos expression and its potential role in the growth of pancreatic carcinoma, we developed a recombinant plasmid, a pEGFP-N1-Net, which codes for Net-EGFP fusion proteins, and stably transfected it into BxPC-3 human pancreatic carcinoma cells. Using stable transformants, we were able to show that overexpression of Net decreased the expression of c-fos and inhibited pancreatic cancer cell proliferation. Cell cycle analysis demonstrated that Net overexpression inhibited cell cycle progression. These findings suggested that loss of Net repression could augment c-fos expression and further trigger neoplastic cell proliferation, which was involved in the pathogenesis of pancreatic cancer. Therefore, Net might be a potential target for the treatment of c-fos-positive pancreatic cancer.

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Structure and function of helix-loop-helix proteins

Cited by 444 publications

References 51 publications

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes

Pancreatic β-Cell-specific Repression of Insulin Gene Transcription by CCAAT/Enhancer-binding Protein β

Growth Inhibitory Effect of the Ternary Complex Factor Net on Human Pancreatic Carcinoma Cell Lines

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