Three-dimensionally Specific Inhibition of DNA Repair-Related Genes by Activated KRAS in Colon Crypt Model

TAL1 plays pivotal roles in vascular and hematopoietic developments through the complex with LMO2 and GATA1. Hemangioblasts, which have a differentiation potential for both endothelial and hematopoietic lineages, arise in the primitive streak and migrate into the yolk sac to form blood islands, where primitive hematopoiesis occurs. ZFAT (a zinc-finger gene in autoimmune thyroid disease susceptibility region / an immune-related transcriptional regulator containing 18 C 2 H 2 -type zinc-finger domains and one AT-hook) was originally identified as an immune-related transcriptional regulator containing 18 C 2 H 2 -type zinc-finger domains and one AT-hook, and is highly conserved among species. ZFAT is thought to be a critical transcription factor involved in immune-regulation and apoptosis; however, developmental roles for ZFAT remain unknown. Here we show that Zfat -deficient ( Zfat −/− ) mice are embryonic-lethal, with impaired differentiation of hematopoietic progenitor cells in blood islands, where ZFAT is exactly expressed. Expression levels of Tal1 , Lmo2 , and Gata1 in Zfat −/− yolk sacs are much reduced compared with those of wild-type mice, and ChIP-PCR analysis revealed that ZFAT binds promoter regions for these genes in vivo. Furthermore, profound reduction in TAL1, LMO2, and GATA1 protein expressions are observed in Zfat −/− blood islands. Taken together, these results suggest that ZFAT is indispensable for mouse embryonic development and functions as a critical transcription factor for primitive hematopoiesis through direct-regulation of Tal1 , Lmo2 , and Gata1. Elucidation of ZFAT functions in hematopoiesis might lead to a better understanding of transcriptional networks in differentiation and cellular programs of hematopoietic lineage and provide useful information for applied medicine in stem cell therapy.

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“…Real-time qRT-PCR was performed as previously described (52). The primer set ID for the assay is listed in Dataset S1.…”

Section: Methodsmentioning

confidence: 99%

Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands

Tsunoda

Takashima

Tanaka

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Nearly 100% transfection efficiency was achieved in the HUVECs with the control miRNA, ZFAT-miRNA-1 and ZFAT-miRNA-2. The immunofluorescence experiment was done as described previously [20].…”

Section: Western Blottingmentioning

confidence: 99%

ZFAT is essential for endothelial cell assembly and the branch point formation of capillary-like structures in an angiogenesis model

Yoshida¹,

Tsunoda²,

Takashima³

et al. 2010

Cellular and Molecular Biology Letters

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ZFAT, originally identified as a susceptibility gene for autoimmune thyroid disease, encodes a transcriptional regulator with one AT-hook and 18 C 2 H 2 -type zinc-finger domains. It is highly conserved among species. Here, we demonstrate that ZFAT is clearly expressed in human umbilical vein endothelial cells (HUVECs). Furthermore, we show that endothelial cell assembly and the branch point formation of capillary-like structures in HUVECs is impaired by the reduction of ZFAT expression through the use of ZFAT-miRNAs, whereas differences in cell proliferation or apoptotic features were not observed after the reduction in ZFAT expression. These results suggest that ZFAT may have critical roles in the capillary-like network formation that is involved in vascular remodeling. Elucidating the ZFAT-mediated transcriptional network will lead to a better understanding of the molecular mechanisms of angiogenesis.

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“…PI3K/Akt activation promotes the phosphorylation of DNA-PK, and may thus regulate the repair of DNA damage by controlling DNA-PK activity [42]. In vitro, KRAS mutation leads to downregulation of the DNA repair-related tumor suppressor genes TP53, BRCA1, BRCA2, and EXO1 [43]. The p53, BRCA1, BRCA2, and Exo1 proteins play a key role in the repair of double-strand breaks by homologous recombination [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer

Devun

Bousquet²,

Biau

et al. 2011

J Gastroenterol

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Three-dimensionally Specific Inhibition of DNA Repair-Related Genes by Activated KRAS in Colon Crypt Model

Cited by 43 publications

References 41 publications

Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands

Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands

ZFAT is essential for endothelial cell assembly and the branch point formation of capillary-like structures in an angiogenesis model

Preclinical study of the DNA repair inhibitor Dbait in combination with chemotherapy in colorectal cancer

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