Role of the CCAAT/Enhancer Binding Protein-α Transcription Factor in the Glucocorticoid Stimulation of p21 Gene Promoter Activity in Growth-arrested Rat Hepatoma Cells

Cram, Erin J.; Ramos, Ross A.; Wang, Edward C.; Helen, H.; Nishio, Yukihiro; Firestone, Gary L.

doi:10.1074/jbc.273.4.2008

Cited by 115 publications

(104 citation statements)

References 51 publications

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“…The generation of knockout mouse models suggested that C/EBP␣ is necessary to decrease hepatocyte proliferation in newborn animals (11,34), while the deletion of C/EBP␤ had no effect on liver proliferation (28). One possible pathway of C/EBP␣-mediated growth arrest in newborn mice has been suggested by the observation that C/EBP␣ regulates the cyclindependent kinase inhibitor p21 (5,34,36). However, measurements of PCNA levels in p21 knockout mice (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…C/EBP␣ expression is induced in the liver before birth (2) and correlates with the inhibition of hepatocyte proliferation in newborn mice (11,34). p21 protein is coordinately expressed in the liver (5,29,34) and is likely to be controlled by C/EBP␣ through the stabilization of the p21 protein (34). Overexpression of p21 inhibited liver proliferation during prenatal development (42); however, the expression of endogenous p21 during prenatal development has not been described.…”

Section: Resultsmentioning

confidence: 99%

“…The transcriptional regulation of specific genes by C/EBP␣ has been found to be a major mechanism in the control of adipose tissue differentiation and energy metabolism. However, the regulation of cell proliferation by C/EBP␣ is more complicated and involves both transcriptional control (3,5,36) and interaction with proteins that regulate cell cycle progression (34). The expression of C/EBP␣ and C/EBP␤ proteins has been shown to be increased in the liver before birth (2).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that C/EBP␣ up-regulates p21 mRNA transiently, but protein level elevation occurs primarily via the stabilization of p21 protein (36). It has been recently shown that C/EBP␣ can also up-regulate p21 protein in hepatoma cells (3,5). In the liver, C/EBP␣ regulates p21 protein levels presumably through a protein-protein interaction (34).…”

mentioning

confidence: 99%

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C/EBPα Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

Timchenko

Wilde

Darlington

1999

Molecular and Cellular Biology

104

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We previously showed that the rate of hepatocyte proliferation in livers from newborn C/EBP␣ knockout mice was increased. An examination of cell cycle-related proteins showed that the cyclin-dependent kinase (CDK) inhibitor p21 level was reduced in the knockout animals compared to that in wild-type littermates. Here we show additional cell cycle-associated proteins that are affected by C/EBP␣. We have observed that C/EBP␣ controls the composition of E2F complexes through interaction with the retinoblastoma (Rb)-like protein, p107, during prenatal liver development. S-phase-specific E2F complexes containing E2F, DP, cdk2, cyclin A, and p107 are observed in the developing liver. In wild-type animals these complexes disappear by day 18 of gestation and are no longer present in the newborn animals. In the C/EBP␣ mutant, the S-phase-specific complexes do not diminish and persist to birth. The elevation of levels of the S-phase-specific E2F-p107 complexes in C/EBP␣ knockout mice correlates with the increased expression of several E2F-dependent genes such as those that encode cyclin A, proliferating cell nuclear antigen, and p107. The C/EBP␣-mediated regulation of E2F binding is specific, since the deletion of another C/EBP family member, C/EBP␤, does not change the pattern of E2F binding during prenatal liver development. The addition of bacterially expressed, purified His-C/EBP␣ to the E2F binding reaction resulted in the disruption of E2F complexes containing p107 in nuclear extracts from C/EBP␣ knockout mouse livers. Ectopic expression of C/EBP␣ in cultured cells also leads to a reduction of E2F complexes containing Rb family proteins. Coimmunoprecipitation analyses revealed an interaction of C/EBP␣ with p107 but none with cdk2, E2F1, or cyclin A. A region of C/EBP␣ that has sequence similarity to E2F is sufficient for the disruption of the E2F-p107 complexes. Despite its role as a DNA binding protein, C/EBP␣ brings about a change in E2F complex composition through a protein-protein interaction. The disruption of E2F-p107 complexes correlates with C/EBP␣-mediated growth arrest of hepatocytes in newborn animals.

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Section: Discussionmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

C/EBPα Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

Timchenko

Wilde

Darlington

1999

Molecular and Cellular Biology

104

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“…Composite GC responsive regions have been described in the promoters of tyrosine aminotransferase (Grange et al, 2001;Grange et al, 1989;Roux et al, 1995;Sassi et al, 1998) proliferin (Diamond et al, 1990), α1-acid glycoprotein (Alam et al, 1993;Nishio et al, 1993;Savoldi et al, 1997), the cyclin-dependent kinase inhibitor p21 waf1/cip1 Cram et al, 1998), β1-adrenergic receptor (Tseng et al, 2001), glucose-6-phosphate transporter (Kallwellis-Opara et al, 2003), pyruvate dehydrogenase kinase 4 (Kwon et al, 2004), monoamine oxidase (Manoli et al, 2005;Ou et al, 2006), β-casein (Rosen et al, 1998;Wyszomierski and Rosen, 2001) and others.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory functions of glucocorticoid-induced genes

Clark

2007

Molecular and Cellular Endocrinology

238

193

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The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress

et al. 2017

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Activating transcription factor 4 (ATF4) is well known for its role in the endoplasmic reticulum (ER) stress response. ATF4 also transcriptionally induces multiple effectors that determine cell fate depending on cellular context. In addition, ATF4 can communicate both pro-apoptotic and pro-survival signals. How ATF4 mediates its prosurvival roles, however, requires further investigation. Here, we report that the CDK inhibitor p21 is a novel target gene of ATF4. We identified two ATF4-responsive elements, one of which directly binds ATF4, within the first intron of the p21 gene. Importantly, overexpression of p21 enhances cell survival following ER stress induction, while p21 knockdown increases cell death. These results suggest that p21 induction plays a vital role in the cellular response to ER stress and indicate that p21 is a prosurvival effector of ATF4.

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Role of the CCAAT/Enhancer Binding Protein-α Transcription Factor in the Glucocorticoid Stimulation of p21 Gene Promoter Activity in Growth-arrested Rat Hepatoma Cells

Cited by 115 publications

References 51 publications

C/EBPα Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

C/EBPα Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

Anti-inflammatory functions of glucocorticoid-induced genes

The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress

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