Activation of p21/ gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α

Chiba, Hideki; Itoh, Tsutomu; Satohisa, Seiro; Sakai, Naoyuki; Noguchi, Hiroko; Osanai, Makoto; Kojima, Takashi; Sawada, Norimasa

doi:10.1016/j.yexcr.2004.08.014

Cited by 49 publications

(45 citation statements)

References 65 publications

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“…24 HNF4␣ has already been shown to increase expression of the p21 gene by antagonizing cMyc activation. 21,25,26 Furthermore, for control of apolipoprotein C III expression, a competition is present between c-Myc and HNF4␣, indicating that HNF4␣ and c-Myc compete for control of the genes involved in cell proliferation as well as differentiation. 27 In our study, we demonstrated that both protein p21 and apolipoprotein C III were raised in hepatoma cells along with increased HNF4␣ expression.…”

Section: Discussionmentioning

confidence: 99%

Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene

Yin¹,

Lin²,

Zhang³

et al. 2008

Hepatology

178

184

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Previous studies have shown that hepatocyte nuclear factor-4␣ (HNF4␣) is a central regulator of differentiated hepatocyte phenotype and forced expression of HNF4␣ could promote reversion of tumors toward a less invasive phenotype. However, the effect of HNF4␣ on cancer stem cells (CSCs) and the treatment of hepatocellular carcinoma (HCC) with HNF4␣ have not been reported. In this study, an adenovirus-mediated gene delivery system, which could efficiently transfer and express HNF4␣, was generated to determine its effect on hepatoma cells (Hep3B and H epatocellular carcinoma (HCC) is one of the most common cancers worldwide, and in the United States its incidence has increased by more than 90% in the past three decades. 1 Despite great advances in detection and treatment of the disease, the mortality rate remains high-especially in the advanced stage, when the disease is usually diagnosed. Even if anticancer therapies could shrink primary and metastatic tumors, such effects are usually transient, and most metastatic cancers relapse frequently.Recent evidence has demonstrated that tumors are organized in a hierarchy of heterogeneous cell populations with different biologic properties and that the populations consist of cancer stem cells (CSCs), proliferating Abbreviations: CSC, cancer stem cell; GFP, green fluorescent protein; HCC, hepatocellular carcinoma; HNF4␣, mRNA, messenger RNA; PBS, PCR, polymerase chain reaction; From the

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Section: Discussionmentioning

confidence: 99%

Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene

Yin¹,

Lin²,

Zhang³

et al. 2008

Hepatology

178

184

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“…A major transcriptional activator of p21 is the tumor suppressor p53, which binds specific sites within the p21 promoter (2). However, several lines of evidence suggest that the transcriptional activity of the p21 promoter can be induced in a variety of cell types by several transcription factors other than p53 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Here, we observed that curcumin induced the transcriptional activation of p21 in U-87MG human glioblastoma cells without significantly affecting the expression and cis-acting activity of p53, which suggests that curcumin-induced p21 expression is independent of p53.…”

Section: Discussionmentioning

confidence: 99%

“…Although p21 expression was initially identified as being p53-dependent, a variety of transcription factors, including SP1/SP3, Smads, AP2, p150(Sal2), the vertebrate homologue of the Drosophila melanogaster homeotic transcription factor Spalt, sterol regulatory element-binding protein-1a, STATs, ets-related transcription factor E1AF, AP2, CAAT/enhancer binding protein a/h, Ets-1, and hepatocyte nuclear factor-4a, bind to specific cis-acting elements in the p21 promoter to activate transcription of the gene via a p53-independent mechanism (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In addition, the region between À58 and À51 bp from the p21 transcription initiation site contains consensus early growth response-1 (Egr-1) binding sequences (EBS), which play a major role in regulating p21 transcription in response to resveratrol treatment in K562 cells (13) and to tamoxifen in MDA-MB-361 breast cancer cells (14).…”

Section: Introductionmentioning

confidence: 99%

p21Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Expression

et al. 2008

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Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1 . Both p53-dependent and p53-independent mechanisms regulate p21Waf1/Cip1 expression, but the mechanism by which curcumin regulates p21Waf1/Cip1 expression remains unknown. Here, we report that transcription of the p21Waf1/Cip1 gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells. Egr-1 is a transcription factor that helps regulate differentiation, growth, and apoptosis in many cell types. Egr-1 expression is induced by curcumin through extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK), but not the p38, mitogen-activated protein kinase (MAPK) pathways, which mediate the transactivation of Elk-1. Transient expression of Egr-1 enhanced curcumin-induced p21 Waf1/Cip1 promoter activity, whereas suppression of Egr-1 expression by small interfering RNA abrogated the ability of curcumin to induce p21 Waf1/Cip1 promoter activity. In addition, stable knockdown of Egr-1 expression in U-87MG cells suppressed curcumin-induced p21 expression. Our results indicate that ERK and JNK MAPK/Elk-1/Egr-1 signal cascade is required for p53-independent transcriptional activation of p21 Waf1/Cip1 in response to curcumin in U-87MG human glioblastoma cells. [Cancer Res 2008;68(5):1369-77]

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“…It is an essential factor for organ development and differentiation of hepatocytes (1)(2)(3)(4). This factor targets a large number of genes involved in various metabolic pathways including carbohydrate, lipid, steroid, xenobiotic, and amino acid metabolism (5,6).…”

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confidence: 99%

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Niehof

Borlak

2008

Diabetes

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OBJECTIVE-The nuclear receptor hepatic nuclear factor 4␣ (HNF4␣) is a master regulatory protein and an essential player in the control of a wide range of metabolic processes. Dysfunction of HNF4␣ is associated with metabolic disorders including diabetes. We were particularly interested in investigating molecular causes associated with diabetic nephropathy.RESEARCH DESIGN AND METHODS-Novel disease candidate genes were identified by the chromatin immunoprecipitation-cloning assay and by sequencing of immunoprecipitated DNA. Expression of candidate genes was analyzed in kidney and liver of Zucker diabetic fatty (ZDF) and of streptozotocin (STZ)-administered rats and after siRNA-mediated silencing of HNF4␣.RESULTS-We identified the calcium-permeable nonselective transient receptor potential cation channel, subfamily C, member 1 (TRPC1) as a novel HNF4␣ gene target. Strikingly, TRPC1 is localized on human chromosome 3q22-24, i.e., a region considered to be a hotspot for diabetic nephropathy. We observed a significant reduction of TRPC1 gene expression in kidney and liver of diabetic ZDF and of STZ-administered rats as a result of HNF4␣ dysfunction. We found HNF4␣ and TRPC1 protein expression to be repressed in kidneys of diabetic patients diagnosed with nodular glomerulosceloris as evidenced by immunohistochemistry. Finally, siRNA-mediated functional knock down of HNF4␣ repressed TRPC1 gene expression in cell culture experiments.CONCLUSIONS-Taken collectively, results obtained from animal studies could be translated to human diabetic nephropathy; there is evidence for a common regulation of HNF4␣ and TRPC1 in human and rat kidney pathologies. We propose dysregulation of HNF4␣ and TRPC1 as a possible molecular rationale in diabetic nephropathy.

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Activation of p21/ gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α

Cited by 49 publications

References 65 publications

Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene

Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene

p21Waf1/Cip1 Expression by Curcumin in U-87MG Human Glioma Cells: Role of Early Growth Response-1 Expression

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

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