Expression of the Transcriptional Repressor Protein Kid-1 Leads to the Disintegration of the Nucleolus

Huang, Zhiqing; Philippin, Bärbel; O’Leary, Eileen; Bonventre, Joseph V.; Kriz, Wilhelm; Witzgall, Ralph

doi:10.1074/jbc.274.12.7640

Cited by 20 publications

(14 citation statements)

References 61 publications

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“…The Kid-1 protein, for example, is found extensively within the nucleolus of transfected cells (Fig. 8I to L) (17). Together, these results demonstrate that KS1 and KAP-1 are localized within similar regions of the nucleus, a finding that is consistent with the ability of these two proteins to interact in GST pulldown assays.…”

Section: Resultssupporting

confidence: 73%

“…8, KS1 and KAP-1 are similarly distributed within discrete regions of the nucleus. This pattern of expression is not observed for all KRAB-ZFPs, as several members of this family have been localized to the nucleolus (17). The Kid-1 protein, for example, is found extensively within the nucleolus of transfected cells (Fig.…”

Section: Resultsmentioning

confidence: 92%

“…In light of our finding that KS1 can function as a sequence-specific transcription factor, it is useful to review the proposed cellular functions for other members of the KRAB-ZFP family. The Kid-1 ZFP, for example, can bind to heteroduplex DNA structures and is localized to the nucleolus (9,17). Once localized to this region of the nucleus, Kid-1 leads to the disintegration of the nucleolus, and nucleolar run-on assays demonstrated that rRNA synthesis was greatly reduced in cells transfected with this protein (17).…”

Section: Discussionmentioning

confidence: 99%

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Sequence-Specific Transcriptional Repression by KS1, a Multiple-Zinc-Finger–Krüppel-Associated Box Protein

Gebelein¹,

Urrutia

2001

Mol Cell Biol

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The vertebrate genome contains a large number of Krüppel-associated box-zinc finger genes that encode 10 or more C 2 -H 2 zinc finger motifs. Members of this gene family have been proposed to function as transcription factors by binding DNA through their zinc finger region and repressing gene expression via the KRAB domain. To date, however, no Krüppel-associated box-zinc finger protein (KRAB-ZFP) and few proteins with 10 or more zinc finger motifs have been shown to bind DNA in a sequence-specific manner. Our laboratory has recently identified KS1, a member of the KRAB-ZFP family that contains 10 different C 2 -H 2 zinc finger motifs, 9 clustered at the C terminus with an additional zinc finger separated by a short linker region. In this study, we used a random oligonucleotide binding assay to identify a 27-bp KS1 binding element (KBE). Reporter assays demonstrate that KS1 represses the expression of promoters containing this DNA sequence. Deletion and site-directed mutagenesis reveal that KS1 requires nine C-terminal zinc fingers and the KRAB domain for transcriptional repression through the KBE site, whereas the isolated zinc finger and linker region are dispensable for this function. Additional biochemical assays demonstrate that the KS1 KRAB domain interacts with the KAP-1 corepressor, and mutations that abolish this interaction alleviate KS1-mediated transcriptional repression. Thus, this study provides the first direct evidence that a KRAB-ZFP binds DNA to regulate gene expression and provides insight into the mechanisms used by multiple-zinc-finger proteins to recognize DNA sequences.

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Sequence-Specific Transcriptional Repression by KS1, a Multiple-Zinc-Finger–Krüppel-Associated Box Protein

Gebelein¹,

Urrutia

2001

Mol Cell Biol

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“…As ZKSCAN4 did not co-localize with Y12, a role in splicing seemed improbable. Another established role for similar proteins, which was also recently claimed for ZKSCAN4, is in transcriptional repression by several mechanisms (Huang et al 1999, Hennemann et al 2003, Li et al 2007). To assess a potential effect on glucocorticoid-dependent transcription, we tested the effect of ZKSCAN4 on a luciferase reporter construct driven by the glucocorticoid-responsive MMTVpromoter in a transient transfection assay.…”

Section: Chromatin-dependent Inhibition Of Gr-mediated Transactivationmentioning

confidence: 99%

A RAS recruitment screen identifies ZKSCAN4 as a glucocorticoid receptor-interacting protein

Ecker¹,

Lorenz²,

Wolf³

et al. 2008

Journal of Molecular Endocrinology

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To search for proteins interacting with the glucocorticoid receptor, we adapted Aronheim's reverse RAS recruitment system relying on the Saccharomyces cerevisiae mutant cdc25-2, which has a temperature-dependent defect in its RAS signaling pathway driving proliferation. The full-length human glucocorticoid receptor (NR3C1, isoform-a) was attached to the yeast plasma membrane in either of two orientations and used as bait to screen a HeLa cell cDNA library. Library proteins were fused to constitutively active, soluble human RAS, complementing the defective yeast pathway in case of bait-prey interaction. Screening of 800 000 clones resulted in the isolation of 21 proteins, 8 of which were followed up to evaluate interaction with the receptor in human cell lines. One of these candidates, the SCAN-and KRAB-domaincontaining zinc finger protein 307 (ZKSCAN4) was co-precipitated with the receptor when both proteins were overexpressed in HEK293 cells. Rabbit antisera against ZKSCAN4 were raised, affinity purified, and used to immunoprecipitate endogenous ZKSCAN4 from Hct116 cells, resulting in co-precipitation of endogenous glucocorticoid receptor. Overexpressed ZKSCAN4 was found to co-localize in granular nuclear structures with the activated glucocorticoid receptor and partially with chromatin regions characterized by histone H3 mono-methylated on lysine 4 (H3K4me1). Overexpressed ZKSCAN4 had no effect on an episomal glucocorticoid receptor-driven reporter plasmid. By contrast, ZKSCAN4 markedly reduced glucocorticoid induction of the mouse mammary tumor virus-promoter-driven reporter gene when this was chromosomally integrated, arguing for a chromatin-dependent inhibition of glucocorticoid receptor-mediated transactivation.

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“…The rat Kid-1 protein, which is a 66-kDa protein with KRAB domains at the NH 2 terminus and two C2H2 zinc finger clusters of four and nine zinc fingers at the COOH terminus, functions as a transcriptional factor in the kidney development. [25][26][27] Furthermore, all of HZF1, CROL, ZFP35 and Kid-1 have the same conserved domain consisting of zinc finger motifs, which is often used in DNA recognition and also in protein-protein interactions. The similarity among the four proteins implicates that HZF1 functions in the hematopoiesis possibly through the regulation mechanisms similar to that proposed for those three proteins.…”

Section: New Zinc Finger Protein Hzf1 and Its Function H Peng Et Almentioning

confidence: 99%

Identification and characterization of a novel zinc finger protein (HZF1) gene and its function in erythroid and megakaryocytic differentiation of K562 cells

Han

Zhang

2006

Leukemia

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A novel zinc finger protein (HZF1) gene was identified and characterized by screening a human bone marrow cDNA library, using a new expression sequence tag probe that contains sequences encoding zinc finger motifs. There are at least three transcripts that may result from different splicing of the pre-mRNA, but the differences among them are only involved in 5 0 non-translation region of HZF1 mRNA. HZF1 gene contains four exons and three introns. The putative protein consists of 670 amino-acid residues including 15 typical C2H2 and 2 C2RH zinc finger motifs. This structure characterization of HZF1 and the nuclear location of the protein suggest that HZF1 may function as a transcription factor. HZF1 mRNA expression was detected in ubiquitous tissues and various hematopoietic cell lines. Increased HZF1 mRNA expression was observed following erythroid differentiation of K562 cells induced by hemin or megakaryocytic differentiation of K562 cells induced by phorbol myristate acetate (PMA). Both of the antisense method and RNA interference assay revealed that repression of the intrinsic expression of HZF1 blocked the hemin-induced erythroid differentiation and reduced the PMA-induced megakaryocytic differentiation of K562 cells, which suggested that HZF1 play important roles in erythroid and megakaryocytic differentiation.

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Expression of the Transcriptional Repressor Protein Kid-1 Leads to the Disintegration of the Nucleolus

Cited by 20 publications

References 61 publications

Sequence-Specific Transcriptional Repression by KS1, a Multiple-Zinc-Finger–Krüppel-Associated Box Protein

Sequence-Specific Transcriptional Repression by KS1, a Multiple-Zinc-Finger–Krüppel-Associated Box Protein

A RAS recruitment screen identifies ZKSCAN4 as a glucocorticoid receptor-interacting protein

Identification and characterization of a novel zinc finger protein (HZF1) gene and its function in erythroid and megakaryocytic differentiation of K562 cells

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