Biomedical subjects

Leo A van Grunsven

Publications and source records attributed to Leo A van Grunsven.

9 recordsLinked to original sources

PubMed2006

deltaEF1 and SIP1 are differentially expressed and have overlapping activities during Xenopus embryogenesis.

The zinc finger/homeo-domain transcription factor (zfh x 1) family in vertebrates consists of two members, deltaEF1 and SIP1. They have been proposed to display antagonistic activities in the interpretation of Smad-dependent TGFbeta signaling during mesoderm formation. We cloned Xenopus deltaEF1 cDNA, analyzed the expression profile of the gene, and compared the inducing and interacting properties of the protein to that of XSIP1. Whereas XSIP1 RNA is selectively expressed in the early developing nervous system, we show that XdeltaEF1 gene transcription is only activated during neurulation and that its expression is restricted to the paraxial mesoderm. From early tail bud stage, XdeltaEF1 and XSIP1 are coexpressed in migratory cranial neural crest, in the retina, and in the neural tube. Overproduction of XdeltaEF1 in RNA-injected embryos, like that of XSIP1, reduced the expression of BMP-dependent genes but only XSIP1 has the ability to induce neural markers. We find that XdeltaEF1 and XSIP1 can both form complexes, although with different efficiency, with Smad3, with the coactivators p300 and pCAF, and with the corepressor CtBP1. Together, these results indicate that deltaEF1 and SIP1 do not function as antagonists during Xenopus early embryogenesis but do display different repression efficiencies and interaction properties.

Amino Acid Sequence↗

PubMed2005

NIR is a novel INHAT repressor that modulates the transcriptional activity of p53.

Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel transcriptional corepressor with inhibitor of histone acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood. NIR is a potent transcriptional corepressor that is not blocked by histone deacetylase inhibitors and is capable of silencing both basal and activator-driven transcription. NIR directly binds to nucleosomes and core histones and prevents acetylation by histone acetyltransferases, thus acting as a bona fide INHAT. Using a tandem affinity purification approach, we identified the tumor suppressor p53 as a NIR-interacting partner. Association of p53 and NIR was verified in vitro and in vivo. Upon recruitment by p53, NIR represses transcription of both p53-dependent reporters and endogenous target genes. Knock-down of NIR by RNA interference significantly enhances histone acetylation at p53-regulated promoters. Moreover, p53-dependent apoptosis is robustly increased upon depletion of NIR. In summary, our findings describe NIR as a novel INHAT that plays an important role in the control of p53 function.

Animals↗

PubMed2005

Smicl is a novel Smad interacting protein and cleavage and polyadenylation specificity factor associated protein.

Ligand-bound receptors of the Transforming Growth Factor-beta (TGF-beta) family promote the formation of complexes between Smad proteins that subsequently accumulate in the nucleus and interact there with other transcriptional regulators, leading to modulation of target gene expression. We identified a novel nuclear protein, Smicl, which binds to Smad proteins. Smicl and Smads cooperate and enhance TGF-beta mediated activation of a Smad-responsive reporter gene. A domain with five CCCH-type zinc fingers in Smicl is structurally and functionally, at least in vitro, similar to a domain in CPSF-30, the 30 kDa subunit of Cleavage and Polyadenylation Specificity Factor (CPSF). Like CPSF-30, Smicl can associate with some other CPSF subunits characterized previously. Its effect on the induction of a reporter gene for TGF-beta requires the cleavage/polyadenylation signal downstream of the coding sequence of that gene. Thus, Smicl is a novel protein that displays CPSF-30-like activities, interacts in the nucleus with activated Smads, and potentiates in TGF-beta stimulated cells Smad-dependent transcriptional responses, possibly in conjunction with the activity of CPSF complexes.

Activin Receptors, Type I↗

PubMed2004

Direct regulation of the Nrarp gene promoter by the Notch signaling pathway.

Nrarp encodes for an evolutionarily conserved small ankyrin repeat-containing protein that functions as a negative regulator of Notch signaling. Interestingly, increased Nrarp transcription was observed following induction of Notch signaling, suggesting the existence of a negative feedback loop. We show here that both mouse and human promoter regions of Nrarp share two conserved regions located approximately 2 and approximately 3 kb upstream of the transcription start site each containing a perfect putative binding site for the Notch-dependent transcription factor Su(H). A 4.4 kb genomic fragment of the mouse Nrarp locus containing those conserved regions and fused to a luciferase reporter gene showed basal promoter activity in 293T cells and this activity was strongly increased by the intracellular domain of Notch, NICD. NICD-dependent stimulation was attenuated by a dominant negative mutant of Su(H), Su(H)DBM, and was not observed in Su(H)-deficient cells (OT-11). Promoter bashing and gel shift assays revealed that the most distal putative Su(H) binding site located within the -3 kb conserved element plays a crucial role in this induction. Collectively, these results provide definitive support for direct regulation of the Nrarp gene by the Notch pathway.

Animals↗

PubMed2003

Cdyl: a new transcriptional co-repressor.

Cdyl (chromodomain-Y-like) is a chromodomain-containing protein that is predominantly expressed during mouse spermiogenesis. In its carboxy-terminal portion, there is a domain with homology to the coenzyme A (CoA) pocket of the enoyl-CoA hydratase/isomerase, which is shown here to be able to bind CoA and histone deacetylases (HDACs). It also efficiently represses transcription. Moreover, the binding of Hdac1 represses the ability of Cdyl to bind CoA, and a Cdyl-CoA interaction only occurs in the absence of HDACs. These data suggest that Cdyl is primarily a transcriptional co-repressor. However, the degradation of cellular Hdac1 and Hdac2, as observed here in the elongating spermatids, may provide an HDAC-free environment in which Cdyl could bind CoA and participate in the global chromatin remodelling that occurs in these cells.

Amino Acid Sequence↗

PubMed2003

Interaction between Smad-interacting protein-1 and the corepressor C-terminal binding protein is dispensable for transcriptional repression of E-cadherin.

deltaEF1 and SIP1 (or Zfhx1a and Zfhx1b, respectively) are the only known members of the vertebrate Zfh1 family of homeodomain/zinc finger-containing proteins. Similar to other transcription factors, both Smad-interacting protein-1 (SIP1) and deltaEF1 are capable of repressing E-cadherin transcription through binding to the E2 boxes located in its promoter. In the case of deltaEF1, this repression has been proposed to occur via interaction with the corepressor C-terminal binding protein (CtBP). In this study, we show by coimmunoprecipitation that SIP1 and CtBP interact in vivo and that an isolated CtBP-binding SIP1 fragment depends on CtBP for transcriptional repression. However, and most importantly, full-length SIP1 and deltaEF1 proteins do not depend on their interaction with CtBP to repress transcription from the E-cadherin promoter. Furthermore, in E-cadherin-positive kidney epithelial cells, the conditional synthesis of mutant SIP1 that cannot bind to CtBP abrogates endogenous E-cadherin expression in a similar way as wild-type SIP1. Our results indicate that full-length SIP1 can repress E-cadherin in a CtBP-independent manner.

Alcohol Oxidoreductases↗

PubMed2002

Dynamic regulation of Brachyury expression in the amphibian embryo by XSIP1.

Xenopus Brachyury (Xbra) plays a key role in mesoderm formation during early development. One factor thought to be involved in the regulation of Xbra is XSIP1, a zinc finger/homeodomain-like DNA-binding protein that belongs to the deltaEF1 family of transcriptional repressors. We show here that Xbra and XSIP1 are co-expressed at the onset of gastrulation, but that expression subsequently refines such that Xbra is expressed in prospective mesoderm and XSIP1 in anterior neurectoderm. This refinement of the expression patterns of the two genes is due in part to the ability of XSIP1 to repress expression of Xbra. This repression is highly specific, in the sense that XSIP1 does not repress the expression of other regionally expressed genes in the early embryo, and that other members of the family to which XSIP1 belongs, such as deltaEF1 and its Xenopus homologue ZEB, cannot regulate Xbra expression. The function of XSIP1 was studied further by making an interfering construct comprising the open reading frame of XSIP1 fused to the VP16 transactivation domain. Experiments using this chimeric protein suggest that XSIP1 is required for normal gastrulation movements to occur and for the development of the anterior neural plate.

Animals↗

PubMed2002

Complex Smad-dependent transcriptional responses in vertebrate development and human disease.

Smad proteins mediate genomic responses to polypeptides of the transforming growth factor type beta (TGF-beta) family, affecting cellular proliferation and differentiation, adhesion, and death. Members of one class of these Smad proteins, the receptor-regulated Smads or R-Smads, accumulate in the nucleus on their activation by ligand-bound complexes of serine-threonine kinase receptors at the cell surface. These effector proteins then participate directly in the regulation of gene expression by binding to DNA, interacting with transcription factors, and recruiting corepressors or coactivators to specific promoters. Although many nuclear Smad-interacting factors were isolated during the last 3 years, the field has recently taken a step beyond the characterization of the activity of these Smad-containing complexes on gene expression in vitro, as it addresses now their contribution to many processes in vivo. We have selected examples of such recent progress to illustrate the remarkable variation in the molecular mechanisms underlying Smad-dependent signaling depending on the non-Smad partner in the nucleus and their relevance to normal embryogenesis and consequences of their deregulation in human disorders and pathology.

Animals↗

PubMedDate not supplied

Smads and chromatin modulation.

Smad proteins are critical intracellular effector proteins and regulators of transforming growth factor type beta (TGFbeta) modulated gene transcription. They directly convey signals that initiate at ligand-bound receptor complexes and end in the nucleus with changes in programs of gene expression. Activated Smad proteins seem to recruit chromatin modifying proteins to target genes besides cooperating with DNA-bound transcription factors. We survey here the current and still emerging knowledge on Smad-binding factors, and their different mechanisms of chromatin modification in particular, in Smad-dependent TGFbeta signaling.

Animals↗