KRAB-independent suppression of neoplastic cell growth by the novel zinc finger transcription factor KS1.

Gebelein, Brian; Fernández-Zapico, Martín E.; Imoto, Mami; Urrutia, Raúl

doi:10.1172/jci1919

Cited by 45 publications

(47 citation statements)

References 46 publications

(76 reference statements)

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“…To explore the possible mechanism of transcriptional repression mediated by ZNF382, we checked the involvement of heterochromatin silencing, as previous study revealed that KS1 is located in the nucleus and interacts with KAP1 (23,24) whereas KAP1 is known to form a complex with heterochromatin proteins (HP) to exert gene silencing (31). Indirect immunofluorescence staining for Flag-tagged ZNF382 in HCT116 and COS7 cells clearly showed that ZNF382 is a nuclear protein (Fig.…”

Section: Znf382 Represses the Expression Of Multiple Oncogenes Includmentioning

confidence: 93%

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KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas

Cheng¹,

Geng²,

et al. 2010

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Zinc finger transcription factors are involved broadly in development and tumorigenesis. Here, we report that the little studied zinc finger transcription factor ZNF382 functions as a tumor suppressor in multiple carcinomas. Although broadly expressed in normal tissues, ZNF382 expression was attenuated in multiple carcinoma cell lines due to promoter CpG methylation. ZNF382 was also frequently methylated in multiple primary tumors (nasopharyngeal, esophageal, colon, gastric, and breast). Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. We further found that ZNF382 inhibited NF-κB and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-κB upstream factors STAT3, STAT5B, ID1, and IKBKE, most likely through heterochromatin silencing. ZNF382 could suppress tumorigenesis through heterochromatin-mediated silencing, as ZNF382 was colocalized and interacted with heterochromatin protein HP1 and further changed the chromatin modifications of ZNF382 target oncogenes. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas. Cancer Res; 70(16); 6516-26. ©2010 AACR.

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Section: Znf382 Represses the Expression Of Multiple Oncogenes Includmentioning

confidence: 93%

“…KS1, the rat homologue of human ZNF382, is a nuclear protein that functions as a transcription repressor (23,24). We examined the subcellular localization of ZNF382.…”

Section: Znf382 Is a Nuclear Protein Inhibiting The Nf-κb And Ap-1 Simentioning

confidence: 99%

KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas

Cheng¹,

Geng²,

et al. 2010

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“…Reporter Assays-The transcriptional regulatory activity of BTEB3 was determined using the GAL4 assay system, as described previously (10,38). Briefly, CHO cells were co-transfected with the GAL4 expression and reporter plasmids using LipofectAMINE™ (Life Technologies, Inc.).…”

Section: Methodsmentioning

confidence: 99%

The Sp1-like Protein BTEB3 Inhibits Transcription via the Basic Transcription Element Box by Interacting with mSin3A and HDAC-1 Co-repressors and Competing with Sp1

Kaczynski¹,

Zhang²,

Ellenrieder³

et al. 2001

Journal of Biological Chemistry

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Sp1-like proteins are characterized by three conserved C-terminal zinc finger motifs that bind GC-rich sequences found in promoters of numerous genes essential for mammalian cell homeostasis. These proteins behave as transcriptional activators or repressors. Although significant information has been reported on the molecular mechanisms by which Sp1-like activators function, relatively little is known about mechanisms for repressor proteins. Here we report the functional characterization of BTEB3, a ubiquitously expressed Sp1-like transcriptional repressor. GAL4 assays show that the N terminus of BTEB3 contains regions that can act as direct repressor domains. Immunoprecipitation assays reveal that BTEB3 interacts with the co-repressor mSin3A and the histone deacetylase protein HDAC-1. Gel shift assays demonstrate that BTEB3 specifically binds the BTE site, a well characterized GC-rich DNA element, with an affinity similar to that of Sp1. Reporter and gel shift assays in Chinese hamster ovary cells show that BTEB3 can also mediate repression by competing with Sp1 for BTE binding. Thus, the characterization of this protein expands the repertoire of BTEB-like members of the Sp1 family involved in transcriptional repression. Furthermore, our results suggest a mechanism of repression for BTEB3 involving direct repression by the N terminus via interaction with mSin3A and HDAC-1 and competition with Sp1 via the DNA-binding domain.Sp1-like proteins, defined by the presence of three highly homologous C-terminal zinc finger motifs and variant N-terminal domains, are emerging as important regulators of cell homeostasis. Promoters containing Sp1-like sites are essential for the expression of numerous genes necessary for cell cycle progression (1-3), DNA synthesis (4), and other cell processes (5-8), and studies have shown that certain Sp1-like proteins induce apoptosis (9), cell growth inhibition (10 -12), differentiation (13, 14), and carcinogenesis (15). In addition, the disruption of some Sp1-like genes in mice shows that these proteins are critical for normal development (12, 16 -18). Thus, understanding how Sp1-like proteins bind DNA and regulate transcription is important to uncover the molecular mechanisms underlying a large number of cellular events.The existence of at least 17 different Sp1-like proteins offers a significant challenge for understanding how individual members regulate gene expression in a tissue-, cell-, and promoterspecific manner. One mechanism leading to specificity among Sp1-like proteins is a differential pattern of expression. For instance, Sp1, TIEG2, and BTEB1 1 are ubiquitously expressed, whereas the KLF proteins are restricted to certain tissues. Specificity among Sp1-like proteins is also dictated by recognition of DNA. For example, the Sp proteins preferentially bind GC sites (19,20) whereas the KLF subgroup prefers the CA site (21-23). Interestingly, co-expressed Sp1-like proteins exhibiting similar binding specificity, such as Sp1 and Sp3, but often display opposite transcriptional reg...

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“…MAPK/ERK kinase (MEK) inhibitors, PD98059 and U0126, were purchased from Promega (Madison, WI, USA). The expression construct containing the oncogenic H-Ras was generously provided by Dr Raul Urrutia (Gebelein et al, 1998). Complementary DNA (cDNA) clone encoding KLF5 was provided by Dr Jerry Lingrel (Conkright et al, 1999).…”

Section: Reagentsmentioning

confidence: 99%

Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras

et al. 2004

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Previous studies indicate that Kru¨ppel-like factor 5 (KLF5), also known as intestinal-enriched Kru¨ppel-like factor (IKLF), is a positive regulator of cell proliferation and gives rise to a transformed phenotype when overexpressed. Here we demonstrate that levels of KLF5 transcript and protein are significantly elevated in oncogenic H-Ras-transformed NIH3T3 cells. These cells display an accelerated rate of proliferation in both serum-containing and serum-deprived media and form anchorage-independent colonies in soft agar assays. H-Ras-transformed cells also contain elevated mitogenactivated protein kinase (MAPK) activity. When treated with inhibitors of MEK (MAPK kinase), H-Ras-transformed cells lose their growth advantage and no longer form colonies. Significantly, levels of KLF5 transcript and protein are substantially reduced in H-Ras-transformed cells treated with MEK inhibitors. Moreover, inhibition of KLF5 expression in H-Ras-transformed cells with KLF5-specific small interfering RNA (siRNA) leads to a decreased rate of proliferation and a significant reduction in colony formation. H-Ras-transformed cells also contain elevated levels of Egr1 that are diminished by MEK inhibitors. Inhibition of Egr1 by siRNA results in a reduced level of KLF5, indicating that Egr1 mediates the inductive action of MAPK on KLF5. Lastly, KLF5 activates expression of cyclin D1. These findings indicate that the increased expression of KLF5 in H-Rastransformed cells is secondary to increased MAPK activity from H-Ras overexpression and that the elevated level of KLF5 is in part responsible for the proproliferative and transforming activities of oncogenic H-Ras.

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KRAB-independent suppression of neoplastic cell growth by the novel zinc finger transcription factor KS1.

Cited by 45 publications

References 46 publications

KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas

KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas

The Sp1-like Protein BTEB3 Inhibits Transcription via the Basic Transcription Element Box by Interacting with mSin3A and HDAC-1 Co-repressors and Competing with Sp1

Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras

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