Heterogeneous Nuclear Ribonucleoprotein K Is a DNA-binding Transactivator

Tomonaga, Takeshi; Levens, David

doi:10.1074/jbc.270.9.4875

Cited by 173 publications

(178 citation statements)

References 29 publications

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“…Then, HMGB1-hnRNP K interaction may connect two systems, which have a large protein-protein interaction potential, in order to extend their respective domains of action even further. For example, hnRNP K was shown to be a transcription-activating factor for the c-myc promoter (43,44). Although we have not been able to establish a direct connection, it is remarkable that c-myc mRNA levels in HMGB1Ϫ/Ϫ mouse cells are about 5-10-fold lower than those in wild type cells.…”

Section: Discussionmentioning

confidence: 99%

HMGB1 Interacts with Many Apparently Unrelated Proteins by Recognizing Short Amino Acid Sequences

Dintilhac

Bernués

2002

Journal of Biological Chemistry

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The chromatin high mobility group protein 1 (HMGB1) is a very abundant and conserved protein that is structured into two HMG box domains plus a highly acidic C-terminal domain. From the ability to bind DNA nonspecifically and to interact with various proteins, several functions in DNA-related processes have been assigned to HMGB1. Nevertheless, its functional role remains the subject of controversy. Using a phage display approach we have shown that HMGB1 can recognize several peptide motifs. A computer search of the protein data bases found peptide homologies with proteins already known to interact with HMGB1, like p53, and have allowed us to identify new potential candidates. Among them, transcriptional activators like the heterogeneous nuclear ribonucleoprotein K (hnRNP K), repressors like methyl-CpG binding protein 2 (MeCP2), and co-repressors like the retinoblastoma susceptibility protein (pRb) and Groucho-related gene proteins 1 (Grg1) and 5 (Grg5) can be found. A detailed analysis of the interaction of Grg1 with HMGB1 confirmed that the binding region contained the sequence homologous to one of the peptides identified. Our results have led us to propose that HMGB1 may play a central role in the stabilization and/or assembly of several multifunctional complexes through protein-protein interactions.In the eukaryotic cell nucleus of all vertebrate cell types, HMGB1 1 (formerly named HMG1, see Ref. 1 for a revised nomenclature) is one of the most abundant non-histone proteins. HMGB1 has been shown to be essential because knockout mice die 24 h after birth (2). HMGB1 is highly conserved, particularly in mammals and to a lesser extent throughout the animal kingdom. HMGB1 is structured into three domains, two basic HMG boxes (HMG domains A and B) and a highly acidic C-terminal domain, which confer an overall dipolar appearance to this protein (see Refs. 3-5 for reviews). Each of the HMG boxes is formed by two short and one long ␣-helix that upon folding produce an L-or V-shaped three-dimensional domain structure (6 -8). Whereas the acidic C-terminal domain is presumably involved in the modulation of HMGB1 activity, the HMG box domains allow the protein to bind to linear DNA with moderate affinity and to highly structured (3-and 4-way junction DNA, cruciform DNA) or distorted DNA (bent or kink DNA, bulged DNA, cisplatin-modified DNA) with higher affinity, but always without sequence specificity. The concave surface of the L-or V-shaped HMG box domain contacts the DNA in the minor groove in two slightly different ways introducing important modifications in the structure of DNA, in particular a strong bend (reviewed in Ref. 5). Presumably, these features will be of relevance for the biological functions in which HMGB1 has been involved (DNA repair, recombination, replication, and transcription).The activity of HMGB1 is not solely mediated by its ability to bind to DNA. Indeed, HMGB1 and the related HMGB2 protein can interact through their HMG box domains with a broad range of proteins ranging from nuclear cell prote...

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Section: Discussionmentioning

confidence: 99%

HMGB1 Interacts with Many Apparently Unrelated Proteins by Recognizing Short Amino Acid Sequences

Dintilhac

Bernués

2002

Journal of Biological Chemistry

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“…As a positive control, G/hnRNP K/VP16 was also transfected (21). The hnRNP K protein binds sequence specifically to the top single strand of the PuF site in the c-myc promoter and is able to transactivate PuF/CT containing reporters with or without an artificially attached additional activation domain (21)(22)(23)(24)(25). Two elements of the experimental design are noteworthy.…”

Section: Test For Targeting Of Nm23 To Puf/nhe/ct Elements In Vivo-mentioning

confidence: 99%

Nm23/PuF Does Not Directly Stimulate Transcription through the CT Element in Vivo

Michelotti

Sanford

Freije

et al. 1997

Journal of Biological Chemistry

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“…Despite its function in RNA handling, the precise physiological role of hnRNPs has yet to be fully defined and may include transregulatory effects. Recent studies have shown that the hnRNPs D0B, E2BP, and K are able to bind to double-stranded DNA motifs within the complement receptor 2, hepatitis B virus, and c-myc promoters, respectively (33)(34)(35). hnRNPs can also repress viral DNA replication, repress estrogen-and vitamin D-induced transcription, and transcriptionally regulate various genes, including the rat spi2 gene (30, 36 -38).…”

Section: Discussionmentioning

confidence: 99%

S-Nitrosylation of Heterogeneous Nuclear Ribonucleoprotein A/B Regulates Osteopontin Transcription in Endotoxin-stimulated Murine Macrophages

Gao

Guo

Wei

et al. 2004

Journal of Biological Chemistry

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Osteopontin (OPN) is a highly hydrophilic and negatively charged sialoprotein of ϳ298 amino acids that contains a Gly-Arg-Gly-Asp-Ser sequence. It is a secreted protein with diverse regulatory functions, including cell adhesion and migration, tumor growth and metastasis, atherosclerosis, aortic valve calcification, and repair of myocardial injury. Despite the many recognized functions of OPN, very little is known of the transcriptional regulation of OPN. In this regard, we have previously demonstrated that OPN transcription and promoter activity are significantly up-regulated in response to NO in a system of endotoxin-stimulated murine macrophages. However, the specific cis-and trans-regulatory elements that determine the extent of endotoxin-and NO-mediated induction of OPN synthesis are unknown. In this follow-up study, we demonstrate that: 1) OPN gene transcription is regulated by a constitutive transcriptional repressor protein, heterogeneous nuclear ri- Osteopontin (OPN) 1 is a highly hydrophilic and negatively charged sialoprotein of ϳ298 amino acids that contains a GlyArg-Gly-Asp-Ser sequence. It is a secreted protein with diverse regulatory functions, including cell adhesion and migration, tumor growth and metastasis, atherosclerosis, aortic valve calcification, and repair of myocardial injury. Despite the many recognized functions of OPN, very little is known of the transcriptional regulation of OPN. Studies indicate that the OPN promoter contains various motifs including a purine-rich sequence, an Ets-like sequence, glucocorticoid and vitamin D response elements, and interferon-inducible elements (1, 2). In this regard, we have previously demonstrated that OPN transcription and promoter activity are significantly up-regulated in response to NO in a system of endotoxin-stimulated murine macrophages (3). However, the specific cis-and trans-regulatory elements that determine the extent of endotoxin-and NO-mediated induction of OPN synthesis are unknown.In RAW 264.7 and ANA-1 murine macrophages, we have demonstrated that LPS and/or pro-inflammatory cytokine induced NO synthesis is a potent mediator of OPN promoter activation, gene transcription, and protein expression (3). In this study, we demonstrate that: 1) OPN gene transcription is regulated by a constitutive transcriptional repressor protein, heterogeneous nuclear ribonucleoprotein A/B (hnRNP A/B); 2) in vivo hnRNP DNA binding activity is significantly inhibited in the setting of LPS-mediated NO synthesis; and 3) S-nitrosylation of hnRNP A/B at a cysteine residue in the DNA-binding region inhibits in vitro DNA binding activity. Our findings suggest that LPS-induced S-nitrosylation of hnRNP inhibits its activity as a constitutive repressor of the OPN promoter. These data represent a novel function for hnRNP proteins, which are better known as participants in telomere biogenesis, splicing, and mRNA transport. NO Synthesis in RAW 264.7 Macrophages-RAW 264.7 macrophages were maintained in Dulbecco's modified Eagle's medium with 10% heat-inactivated fetal...

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Heterogeneous Nuclear Ribonucleoprotein K Is a DNA-binding Transactivator

Cited by 173 publications

References 29 publications

HMGB1 Interacts with Many Apparently Unrelated Proteins by Recognizing Short Amino Acid Sequences

HMGB1 Interacts with Many Apparently Unrelated Proteins by Recognizing Short Amino Acid Sequences

Nm23/PuF Does Not Directly Stimulate Transcription through the CT Element in Vivo

S-Nitrosylation of Heterogeneous Nuclear Ribonucleoprotein A/B Regulates Osteopontin Transcription in Endotoxin-stimulated Murine Macrophages

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