A Splice Variant of the ITF-2 Transcript Encodes a Transcription Factor That Inhibits MyoD Activity

Skerjanc, Ilona S.; Truong, James; Filion, Pascale; McBurney, Michael W.

doi:10.1074/jbc.271.7.3555

Cited by 64 publications

(54 citation statements)

References 44 publications

(52 reference statements)

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“…Tissue-specific bHLH factors are in vivo expected to heterodimerize mainly with E-proteins, which are alternative splice products of a number of different genes (71,76). The minute yet reproducible activation by Twist1 alone (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Transcriptional Activation by the Proto-oncogene Twist1

Laursen

Mielke

Iannaccone

et al. 2007

Journal of Biological Chemistry

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Mammalian Twist1, a master regulator in development and a key factor in tumorigenesis, is known to repress transcription by several mechanisms and is therefore considered to mediate its function mainly through inhibition. A role of Twist1 as transactivator has also been reported but, so far, without providing a mechanism for such an activity. Here we show that heterodimeric complexes of Twist1 and E12 mediate E-boxdependent transcriptional activation. We identify a novel Twist1 transactivation domain that coactivates together with the less potent E12 transactivation domain. We found three specific residues in the highly conserved WR domain to be essential for the transactivating function of murine Twist1 and suggest an ␣-helical structure of the transactivation domain.When the human genome was sequenced, one of the surprising results was the low number of genes, summing up to only about one-tenth of the expected number. Explanations for this apparent lack of genes were found in differential gene splicing and protein modification as well as in the combinatorial use of regulating signals and transcription factors. A third explanation, multifunctional proteins, has so far received little attention. Here we show that the basic helix-loop-helix (bHLH) 2 protein Twist1, a known transcriptional inhibitor, can also function as an activator, depending on the regulatory sequences of the target genes. Identification of this additional molecular mechanism may aid in explaining the pleiotropic effects of Twist1 in development and in understanding the complex phenotype of the human Saethre-Chotzen syndrome, which is caused by haploid insufficiency of Twist1.Tissue-specifically expressed bHLH transcription factors are important regulators during embryonic development and postnatal life. They mediate their function through binding to DNA elements of the NCANNTGN consensus sequence termed E-boxes (1, 2). The evolutionarily conserved molecular mechanisms leading to DNA binding have been firmly established. In brief, two amphipathic ␣-helices connected by a loop region form the HLH motif, a protein interaction domain through which bHLH factors form homo-or heterodimers. A region of basic residues N-terminal to the HLH motif is necessary for DNA binding. Members of a class of ubiquitously expressed bHLH factors termed E-proteins serve as activating dimerization partners for tissue-specific bHLH factors (3, 4). In general, single E-boxes are sufficient for bHLH responsiveness, yet cooperative binding to dual E-boxes has been observed (5). Id proteins constitute a specific class of inhibitory HLH factors, which are unable to bind DNA due to a lack of basic regions (6). The Id proteins consequently function as negative regulators.Although dimerization and DNA binding are mechanistically similar for all bHLH proteins, the transactivational mechanisms are often of different evolutionary origin. The closely related myogenic bHLH factors Myf5 and MyoD1 both up-regulate muscle-specific genes such as muscle creatine kinase, yet the sequence...

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Section: Discussionmentioning

confidence: 99%

Mechanism of Transcriptional Activation by the Proto-oncogene Twist1

Laursen

Mielke

Iannaccone

et al. 2007

Journal of Biological Chemistry

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“…21 The repeat is transcribed into a prepro-mRNA CTG sequence and could potentially have a role similar to that of the untranslated CTG repeat in myotonic dystrophy (DM). 28 In DM, transcripts containing large CTG repeats are retained in discreet foci in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…CTG18.1 is a particularly interesting locus as it is present within a gene that is expressed in multiple organs including the brain. 21 Furthermore, linkage of BPAD has been reported to the part of chromosome 18 containing the CTG18.1 locus. [22][23][24] Here, we have used PCR to test if these loci contribute to the excess of large RED products found in a previous association study on BPAD patients.…”

Section: Introductionmentioning

confidence: 99%

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

et al. 1998

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An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) Ͼ120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P Ͻ 0.07) with a significantly different size distribution (P Ͻ 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products Ͼ120 nt. The RED product distribution was significantly different (P Ͻ 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P Ͻ 0.04) of CTG18.1 expansions as well as a different (P Ͻ 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (r s = −0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.

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“…There are two main categories of bHLH proteins. The class A bHLH, also known as the E proteins, such as those encoded by di erentially spliced transcripts from the E2A (E12, E47 and E2-5/ITF1 proteins), E2-2/ITF2 and HEB/HTF4 genes and Daughterless are ubiquitously expressed (Murre et al, 1989b;Henthorn et al, 1990;Zhang et al, 1991;Hu et al, 1992;Skerjanc et al, 1996;Massari and Murre, 2000) whereas class B bHLH proteins, which include members such as MyoD, myogenin, NeuroD/BETA2, MASH, HAND and TAL, show a tissue-restricted pattern of expression. Dimerization is essential for DNA binding and transcriptional activity in vivo (Lassar et al, 1991;Massari and Murre, 2000) and in general, class B bHLH proteins form heterodimers with the class A bHLH proteins with few exception, although the latter can also operate as homodimers (Shen and Kadesch, 1995).…”

Section: Introductionmentioning

confidence: 99%

Id proteins in cell cycle control and cellular senescence

2001

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The Id family of helix ± loop ± helix (HLH) proteins are thought to a ect the balance between cell growth and di erentiation by negatively regulating the function of basic ± helix ± loop ± helix (bHLH) transcription factors. Although it has been suggested for some time that Id is involved in cell cycle regulation, little is known about the molecular mechanism of this control. Recent studies, however, have revealed that Id binds to important cell cycle regulatory proteins other than bHLH proteins. Two such proteins, pRB (retinoblastoma tumour suppressor protein) family proteins and Ets-family transcription factors are known to play key roles in cell cycle regulation, transformation and tumour suppression. Through the characterization of these pathways we will begin to understand the mechanisms by which Id controls normal and abnormal cell cycle progression. Oncogene (2001) 20, 8317 ± 8325

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A Splice Variant of the ITF-2 Transcript Encodes a Transcription Factor That Inhibits MyoD Activity

Cited by 64 publications

References 44 publications

Mechanism of Transcriptional Activation by the Proto-oncogene Twist1

Mechanism of Transcriptional Activation by the Proto-oncogene Twist1

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

Id proteins in cell cycle control and cellular senescence

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