Dominant Negative Regulation of the Mouse α-Fetoprotein Gene in Adult Liver

Vacher, Jean; Tilghman, Shirley M.

doi:10.1126/science.1702902

Cited by 123 publications

(96 citation statements)

References 24 publications

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“…[13][14][15][16][17] The AFP gene silencer elements existing between its enhancer and promoter regions play a major role in repressing the AFP gene expression in the low AFP-producing hepatoma cells. 18,19 In addition, McVey et at 10 have recently shown that only a G-to-A substitution at nucleotide −119 in the human AFP promoter is responsible for hereditary persistence of human AFP (HPAFP). In the present study, we constructed the retroviral vector in which the variant-type of the 0.3 kb human AFP promoter with a G-to-A substitution at nucleotide −119, a point mutation relevant to HPAFP, regulates the HSVtk gene expression (LNAFM0.3TK), and evaluated its efficacy in gene therapy for HCC.…”

Section: Discussionmentioning

confidence: 99%

Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma

et al. 1999

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We previously reported that the retroviral vector intermediate AFP-producing cells (PLC/PRF/5). By the (LNAFW0.3TK) expressing the herpes simplex thymidine reporter gene transfection assay, the activity of the variantkinase (HSVtk) gene under the control of the 0.3 kb human type of the promoter was much higher than that of the wild-␣-fetoprotein (AFP) promoter provided the ganciclovir type of the promoter in both HuH-7 and huH-1/cl.2 cells. (GCV)-mediated cytotoxicity in the high AFP-producing Consistent with this, LNAFM0.3TK infection could sensitize (HuH-7) but not in the low AFP-producing (huH-1/cl.2) huH-1/cl.2 cells, as well as HuH-7 and PLC/PRF/5 cells to human hepatoma cells. In the present study, we con-GCV, but did not affect cell growth of nonhepatoma cells structed the retroviral vector (LNAFM0.3TK) in which the (HeLa). In addition, the bystander effect was achieved HSVtk gene expression is regulated by the variant-type of more efficiently by LNAFM0.3TK infection than the 0.3 kb human AFP promoter with a G-to-A substitution LNAFW0.3TK infection in HuH-7 cells. These results sugat nucleotide −119, a point mutation responsible for heredigest that the variant-type of the human AFP promoter tary persistence of human AFP and the vector was applied ensures the therapeutic gene expression in gene therapy to three human hepatoma cell lines, HuH-7, huH-1/cl.2 and particularly for the low AFP-producing hepatoma cells.

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Section: Discussionmentioning

confidence: 99%

Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma

et al. 1999

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“…The AFP gene has three characterized enhancers. These do not appear to be developmentally regulated, because they are strongly active in adult hepatocytes when combined with an active promoter (11)(12)(13).…”

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confidence: 99%

“…The albumin-positive AFP-negative adult hepatocyte phenotype is quite rare in cell lines from all species, except in those derived from the rat Reuber hepatoma. AFP repression is mediated by elements that extend from about Ϫ900 to Ϫ250 bp (12). In the mouse, an upstream part of this repressing region, the SBE/ p53RE (Ϫ878 to Ϫ762) binds p53, p73, and Smad4 (19,20).…”

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Characterization of Distant Enhancers and Promoters in the Albumin-α-Fetoprotein Locus during Active and Silenced Expression

Kajiyama

Tian

Locker

2006

Journal of Biological Chemistry

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The albumin and ␣-fetoprotein genes are adjacent and express closely related serum proteins. Both genes are strongly expressed in fetal liver, primarily through activation by distant enhancers, but the AFP gene selectively undergoes developmental silencing. We used chromatin immunoprecipitation to study enhancers and promoters during active and silenced gene expression. In adult phenotype cells, the silenced AFP gene was actively repressed at the promoter and two proximal enhancers, characterized by the absence of coactivators and acetylated histone 4, and the presence of corepressors and K9-methylated histone 3. Specific transcription factors, TBP, and RNA polymerase II were all detected on both active and silenced genes, indicating that both states were actively regulated. Surprisingly, promoterspecific factors were also detected on enhancers, especially with reduced chromatin shearing. Under these conditions, an enhancer-specific factor was also detected on the albumin promoter. Association of promoter-and enhancer-specific factors was confirmed by sequential immunoprecipitation. Because no binding was detected on intervening segments, these promoter-enhancer associations suggest looping.

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“…A point mutation (G to A) at Ϫ119 of AFP promoter is associated with naturally occurring Hereditary Persistence of AFP (HPAFP), which is predicted to improve HNF-1 binding and decrease NF-1 binding to the mutant sequence (12). The repressor region (Ϫ838 to Ϫ250) is required for AFP postnatal repression in pericentral hepatocytes but not essential for complete AFP repression in the intermediate zone and periportal hepatocytes (7,13). A site in the repressor region can be recognized by p53 family members, which leads to chromatin remodeling and AFP repression (14,15).…”

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confidence: 99%

Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver

Xie¹,

Hai²,

Tsai

et al. 2008

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

119

167

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The alpha-fetoprotein (AFP) gene is highly activated in fetal liver but is dramatically repressed shortly after birth. The mechanisms that underlie AFP transcriptional repression in postpartum liver are not well understood. AFP enhancer, repressor region, and promoter are implicated to be involved in AFP postnatal repression, but the major transcriptional repressor remains undefined. We previously identified a zinc finger protein gene ZBTB20. To determine its physiological functions in vivo, we have generated hepatocyte-specific ZBTB20 knockout mice by the Cre/loxP approach and demonstrated here that ZBTB20 ablation in liver led to dramatic derepression of the AFP gene in entire liver throughout adult life, although the hepatocytes were normally under nonproliferating status. Furthermore, we found that ZBTB20 was a transcriptional repressor capable of specifically inhibiting AFP promoter-driven transcriptional activity. Liver chromatin immunoprecipitation and mobility shift assays showed that ZBTB20 bound to AFP promoter directly. ZBTB20 was developmentally activated in liver after birth and inversely correlated with its AFP gene expression, suggesting that activated ZBTB20 expression in liver mediated AFP gene repression. Our data point to ZBTB20 as a key regulator governing AFP gene transcription and postulate a new model for the postnatal gene repression of AFP in liver.gene regulation ͉ transcription factor ͉ transcriptional repressor

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Dominant Negative Regulation of the Mouse α-Fetoprotein Gene in Adult Liver

Cited by 123 publications

References 24 publications

Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma

Utilization of variant-type of human α-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma

Characterization of Distant Enhancers and Promoters in the Albumin-α-Fetoprotein Locus during Active and Silenced Expression

Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver

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