The homeodomain protein Cux1 interacts with Grg4 to repress p27kip1 expression during kidney development

Sharma, Madhulika; Brantley, Jennifer G.; Vassmer, Dianne; Chaturvedi, Gaurav; Baas, Jennifer; Heuvel, Gregory B. Vanden

doi:10.1016/j.gene.2009.03.014

Cited by 28 publications

(34 citation statements)

References 64 publications

(68 reference statements)

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“…3, G-I). This expression pattern is consistent with findings reported by Sharma et al (53). Terminal nephron differentiation, marked by expression of AQP2 and Na,K-ATPase, is associated with reduced expression of HDAC1 and HDAC2 FIGURE 2.…”

Section: Spatial Expression Of Hdacs In the Developingsupporting

confidence: 92%

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

Chen

Bellew

Xiao

et al. 2011

Journal of Biological Chemistry

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Histone deacetylases (HDACs) regulate fundamental biological processes such as cellular proliferation, differentiation, and survival via genomic and nongenomic effects. This study examined the importance of HDAC activity in the regulation of gene expression and differentiation of the developing mouse kidney. Class I HDAC1-3 and class II HDAC4, -7, and -9 genes are developmentally regulated. Moreover, HDAC1-3 are highly expressed in nephron precursors. Short term treatment of cultured mouse embryonic kidneys with HDAC inhibitors (HDACi) induced global histone H3 and H4 hyperacetylation and H3K4 hypermethylation. However, genome-wide profiling revealed that the HDAC-regulated transcriptome is restricted and encompasses regulators of the cell cycle, Wnt/␤-catenin, TGF-␤/Smad, and PI3K-AKT pathways. Further analysis demonstrated that base-line expression of key developmental renal regulators, including Osr1, Eya1, Pax2/8, WT1, Gdnf, Wnt9b, Sfrp1/2, and Emx2, is dependent on intact HDAC activity. Treatment of cultured embryonic kidney cells with HDACi recapitulated these gene expression changes, and chromatin immunoprecipitation assays revealed that HDACi is associated with histone hyperacetylation of Pax2/Pax8, Gdnf, Sfrp1, and p21. Gene knockdown studies demonstrated that HDAC1 and HDAC2 play a redundant role in regulation of Pax2/8 and Sfrp1 but not Gdnf. Long term treatment of embryonic kidneys with HDACi impairs the ureteric bud branching morphogenesis program and provokes growth arrest and apoptosis. We conclude that HDAC activity is critical for normal embryonic kidney homeostasis, and we implicate class I HDACs in the regulation of early nephron gene expression, differentiation, and survival.Kidney development depends on reciprocal inductive interactions between the metanephric mesenchyme (MM), 4 a specified region in the caudal intermediate mesoderm, and the ureteric bud (UB), an epithelial outgrowth from the Wolffian (nephric) duct (1-3). Recent years have witnessed significant progress in our understanding of the gene regulatory networks of early kidney development (3-6). For example, the Osr1/ Eya1/Pax2/Six/Sall/WT1/Hoxd11 gene regulatory network specifies the MM and is absolutely required for expression of glia-derived neurotrophic factor (Gdnf) (7,8). Gdnf, in turn, is essential for UB outgrowth and subsequent branching (9 -11).Gdnf acts via activation of a c-Ret/PI3K/ERK-dependent gene network (Wnt11, Spry1, Etv4, Etv5, Cxcr4, Myb, Met, and Mmp14) in UB tip cells to control the branching morphogenesis program (12-14). Various growth factor/receptor signaling pathways, including FGFs, bone morphogenic proteins, VEGF, semaphorins, hepatocyte growth factor, EGF, among others, share signaling components with the c-Ret pathway and are required for optimal metanephric growth and patterning (15)(16)(17)(18)(19)(20)(21)(22). Following induction of the MM, activation of the Wnt/␤-catenin signaling pathway plays a key role in nephrogenesis. Release of Wnt9b from the UB branches triggers a ␤-catenindependent mo...

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Section: Spatial Expression Of Hdacs In the Developingsupporting

confidence: 92%

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

Chen

Bellew

Xiao

et al. 2011

Journal of Biological Chemistry

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“…We have recently demonstrated that similar to the Hes, cut homeobox 1 (Cux1) can also associate with TLE protein 4 (TLE4) during kidney development to repress expression of the cyclin kinase inhibitor, p27 [12]. In keeping with the observation that Cux1 is upregulated by Notch intracellular domain, our findings suggested that Cux1 is also an effector of the Notch signaling pathway.…”

Section: Introductionsupporting

confidence: 73%

Activation of Notch signaling pathway in HIV-associated nephropathy

Sharma

Callen

Zhang

et al. 2010

Aids

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Objective HIV-associated nephropathy (HIVAN) is characterized by the development of glomerulosclerosis and is associated with glomerular epithelial cell proliferation. It has recently been shown that activation of the Notch signaling pathway in podocytes results in glomerulosclerosis and podocyte proliferation. To determine whether Notch signaling is involved in renal disorder associated with HIVAN, we evaluated the expression of Notch receptors in HIVAN. Design We evaluated the expression of the Notch signaling pathway using an HIV-transgenic (HIV-Tg) rat model of HIVAN, and biopsy samples from HIVAN and normal controls. Methods Paraffin sections and kidney lysates were used for immunohistochemistry, immunofluorescence and western blot analysis. Results A collapsing variant of glomerulosclerosis and focal segmental sclerosis was observed in HIV-Tg rats. Glomeruli of HIV-Tg rats demonstrated activation of Notch1 and Notch4, as determined by the presence of the intracellular domains. In addition, we observed increased expression of the Notch target protein, hairy enhancer of split homolog-1 in glomeruli of these animals. The expression of the Groucho homolog transducin-like enhancer protein 4, a Notch effector protein, and the homeodomain protein cut homeobox 1 were also significantly increased in glomeruli of HIV-Tg rats, and this was associated with decreased expression of the cyclin kinase inhibitor p27. Intriguingly, renal biopsy samples from HIVAN patients also showed upregulation of cleaved Notch1 and Notch4 in the glomeruli compared with the expression in normal kidneys. Conclusion Our results demonstrate activation of Notch signaling pathway in HIVAN, thereby underscoring its role in disease pathogenesis.

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“…An interaction of CUX1 and HDAC1 has already been postulated in other cell types such as kidney cells and cancer cells, corroborating our findings. 29,42 In line with the concept of CUX1 as a modulator of NF-kB acetylation, Ueda et al 25 described in melanoma cells that CUX1 is able to sequester the acetyltransferase CBP from NFkBp65, leading to reduced acetylation. In our study, we could show that CUX1 decreases induced protein levels of several acetylases, in particular p300, in a TNF-a-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling

et al. 2013

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Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-κB-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-κB p65, leading to reduced binding of NF-κB p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-κB-dependent cytokines.

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The homeodomain protein Cux1 interacts with Grg4 to repress p27kip1 expression during kidney development

Cited by 28 publications

References 64 publications

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

Activation of Notch signaling pathway in HIV-associated nephropathy

CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling

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