C/EBPβ (CCAAT/Enhancer Binding Protein) Controls Cell Fate Determination during Mammary Gland Development

2000 ◽  
Vol 14 (3) ◽  
pp. 359-368 ◽  
Author(s):  
Tiffany N. Seagroves ◽  
John P. Lydon ◽  
Russell C. Hovey ◽  
Barbara K. Vonderhaar ◽  
Jeffrey M. Rosen
Keyword(s):  
Mammary Gland ◽  
Cell Fate ◽  
Binding Protein ◽  
Mammary Glands ◽  
Mammary Development ◽  
Mrna Levels ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Abstract Deletion of the transcription factor CCAAT/enhancer binding protein (C/EBP)β results in a severe inhibition of lobuloalveolar development in the mouse mammary gland. Because progesterone receptor (PR) is requisite for alveolar development, the expression of PR was investigated in C/EBPβ−/− mice. Unexpectedly, the number of PR-positive cells, as well as the levels of PR mRNA, were elevated 3-fold in the mammary glands of C/EBPβ−/− mice. Furthermore, in contrast to wild-type nulliparous mice, in which PR distribution shifted from a uniform to nonuniform pattern between 8–12 weeks of age, C/EBPβ−/− mice exhibited uniform PR distribution throughout all stages of mammary development analyzed. No change in C/EBPβ mRNA levels was observed in the mammary glands of PR−/− mice, suggesting that PR acts in a pathway either in parallel to or downstream of C/EBPβ. The overexpression and disrupted cellular distribution of PR in C/EBPβ−/− mice were coincident with a striking 10-fold decrease in cell proliferation after acute steroid hormone treatment, assayed by incorporation of bromodeoxyuridine. In wild-type mice, PR and bromodeoxyuridine-positive cells were adjacent to each other and rarely colocalized. No differences in the level or pattern of PR expression were observed in the uterus, suggesting that C/EBPβ influences PR in a mam-mary-specific fashion. Together, these data suggest that C/EBPβ may control cell fate decisions in the mammary gland through the appropriate temporal and spatial expression of molecular markers, such as PR, that induce the proliferation of alveolar progenitor cells via juxtacrine mechanisms.

Overexpression of CCAAT Enhancer-Binding Protein α Inhibits the Growth of K562 Cells via the Foxo3a-Bim Pathway

2016 ◽  
Vol 136 (2) ◽  
pp. 65-70 ◽  
Author(s):  
Guili Zhang ◽  
Fei Dong ◽  
Caifu Luan ◽  
Xia Zhang ◽  
Huiyuan Shao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Binding Protein ◽  
K562 Cells ◽  
Cell Counting ◽  
Stable Cell Line ◽  
Mrna Levels ◽  
Forkhead Transcription Factor ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Blood Specimens

We aimed to investigate the role of CCAAT enhancer-binding protein α (C/EBPα) in the pathogenesis of chronic myeloid leukemia (CML) and the mechanism underlying its effect. Bone marrow specimens from 50 patients with CML and peripheral blood specimens from 20 healthy individuals were collected. K562 cells were treated with imatinib. Subsequently, a stable cell line, K562-C/EBPα, was constructed. Cell proliferation was assayed with cell counting kit-8, and mRNA levels of C/EBPα, forkhead transcription factor FKHRL1 (Foxo3a) and Bim were detected by semiquantitative PCR. The correlation of C/EBPα and BCR-ABL was assessed by Spearman's correlation analysis. The results showed that C/EBPα mRNA levels were significantly reduced in CML patients compared with healthy subjects (p < 0.001) and were negatively correlated with BCR-ABL1 (r = -0.5046, p < 0.01). Additionally, imatinib enhanced the expression of C/EBPα in K562 cells compared with untreated cells (p < 0.05). Overexpression of C/EBPα significantly decreased cell proliferation and upregulated the expressions of the apoptosis-related genes Foxo3a (p < 0.01) and Bim (p < 0.05) in K562 cells. In conclusion, C/EBPα expression was decreased in patients with CML. Imatinib enhances the expression of C/EBPα in K562 cells, and the overexpression of C/EBPα inhibits cell proliferation and increases apoptosis via the Foxo3a-Bim pathway.

scholarly journals Intestinal maturation in mice lacking CCAAT/enhancer-binding protein α (C/EPBα)

1998 ◽  
Vol 330 (3) ◽  
pp. 1165-1171 ◽  
Author(s):  
J. Thomas OESTERREICHER ◽  
L. Lucy LEEPER ◽  
J. Milton FINEGOLD ◽  
J. Gretchen DARLINGTON ◽  
J. Susan HENNING
Keyword(s):  
Glucose Transporter ◽  
Binding Protein ◽  
Fatty Acid Binding Proteins ◽  
Mrna Levels ◽  
Fatty Acid Binding ◽  
Proliferative Zone ◽  
Glucose Transporter 2 ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Morphological Maturation

In rodents, there is a surge of intestinal expression of CCAAT/enhancer-binding protein α (C/EBPα) in the late fetal phase just before morphological maturation and the onset of expression of numerous epithelial genes. To investigate directly the hypothesis that C/EBPα plays a causal role in the latter phenomena, we have assessed both structural and functional maturation in neonatal intestine from C/EBPα-null mice and their littermates. No effects of C/EBPα genotype were observed on mucosal architecture or on the size of the proliferative zone in the intestinal crypts. Likewise, the mRNA levels for the glucose transporter 2 (GLUT2), intestinal and liver fatty acid-binding proteins, and apolipoprotein A-IV in newborn intestine were similar in all genotypes. Paradoxically, Na+/glucose co-transporter (SGLT1), lactase phlorizin-hydrolase and apolipoprotein B mRNAs were more abundant in the C/EBPα-deficient animals. In wild-type intestines, C/EBPβ and C/EBPΔ mRNAs were detectable throughout the late fetal period and increased toward term in parallel with C/EBPα mRNA. In newborn intestine, there was no compensatory up-regulation of these isoforms in the C/EBPα-deficient mice. We conclude that C/EBPα has no essential role in morphological maturation of the intestine, the pattern of proliferation of the epithelium, or the onset of expression of this cluster of epithelial mRNAs. However, since other C/EBP isoforms are present in the developing intestine, it is possible that there is a generic requirement for a member of the C/EBP family.

scholarly journals Expression of the genes encoding CCAAT-enhancer binding protein isoforms in the mouse mammary gland during lactation and involution

1998 ◽  
Vol 334 (1) ◽  
pp. 205-210 ◽  
Author(s):  
Georgios SABATAKOS ◽  
Gareth E. DAVIES ◽  
Maria GROSSE ◽  
Anthony CRYER ◽  
Dipak P. RAMJI
Keyword(s):  
Transcription Factors ◽  
Mammary Gland ◽  
Dna Binding ◽  
Binding Protein ◽  
Mouse Mammary Gland ◽  
Binding Activity ◽  
Protein Isoforms ◽  
Dna Binding Activity ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family have been implicated in the activation of gene expression in the mammary gland during lactation. We have therefore investigated the detailed expression profile of the C/EBP family during lactation and involution of the mouse mammary gland. The expression of C/EBPβ and C/EBPδ mRNA was low during lactation, increased dramatically at the beginning of involution and remained constant thereafter. In contrast, C/EBPα mRNA expression was relatively high during the early stages of lactation, declined to low levels during the late stages of lactation and at the start of involution, and increased again during involution. Electrophoretic mobility-shift assays showed a close correlation between the expression of the C/EBP genes and the functional C/EBP DNA-binding activity and, additionally, demonstrated the participation of heterodimers, formed from among the three proteins, in DNA–protein interactions. The DNA-binding activity of the activator protein 1 (AP1) family of transcription factors was also induced during involution. These results therefore point to potentially important regulatory roles for both the C/EBP and the AP1 family during lactation and involution of the mammary gland.

Exchange protein directly activated by cAMP (EPAC) promotes transcriptional activation of the decidual prolactin gene via CCAAT/enhancer-binding protein in human endometrial stromal cells

2018 ◽  
Vol 30 (11) ◽  
pp. 1454
Author(s):  
Kazuya Kusama ◽  
Kazuhiro Tamura ◽  
Hanako Bai ◽  
Toshihiro Sakurai ◽  
Hirotaka Nishi ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Binding Protein ◽  
Luciferase Assay ◽  
Mrna Levels ◽  
Reporter Activity ◽  
Camp Analogue ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Decidual Prolactin ◽  
Exchange Protein

Protein kinase A (PKA) signalling accompanies elevated intracellular cAMP levels during endometrial stromal cell (ESC) decidualisation. Exchange protein directly activated by cAMP (EPAC), an alternate mediator of cAMP signalling, promotes PKA analogue-induced decidualisation; however, the precise mechanism by which EPAC and PKA co-operatively stimulate decidualisation has not been characterised. To examine the role of CCAAT/enhancer-binding protein (C/EBP) in EPAC- and PKA-mediated decidualisation of primary human ESCs, a reporter plasmid containing the 332 bp region upstream from the transcription initiation site of the decidual prolactin (dPRL) gene was generated and the promoter activity was evaluated using a luciferase assay. The dPRL promoter activity was increased by treatment of transfected ESCs with the PKA-selective cAMP analogue N6-phenyl-cAMP (Phe) and enhanced further by co-treatment with the EPAC-selective cAMP analogue 8-(4-chlorophenyltio)-2′-O-methyl cAMP (CPT). Treatment with forskolin, an adenylyl cyclase activator, had a similar effect on reporter activity. Site-directed mutagenesis of the C/EBPβ- and/or C/EBPδ-binding site in the dPRL promoter abolished Phe/CPT-mediated elevation of the reporter activity. EPAC2 knockdown markedly reduced Phe-stimulated C/EBPβ and C/EBPδ mRNA levels, as well as forkhead box O1 (FOXO1) protein levels. These results suggest that EPAC signalling enhances PKA-mediated dPRL expression in ESCs by acting on C/EBP response elements in the promoter region of the gene.

scholarly journals Knockdown of LXRα Inhibits Goat Intramuscular Preadipocyte Differentiation

2018 ◽  
Vol 19 (10) ◽  
pp. 3037 ◽  
Author(s):  
Yan Xiong ◽  
Qing Xu ◽  
Sen Lin ◽  
Yong Wang ◽  
Yaqiu Lin ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Early Stage ◽  
Binding Protein ◽  
Regulatory Element ◽  
Adipogenic Differentiation ◽  
Mrna Level ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Goat intramuscular fat (IMF) content is mainly determined by the processes of intramuscular preadipocytes adipogenic differentiation and mature adipocyte lipid accumulation. However, the underlying regulators of these biological processes remain largely unknown. Here, we report that the expression of Liver X receptor alpha (LXRα) reaches a peak at early stage and then gradually decreases during goat intramuscular adipogenesis. Knockdown of LXRα mediated by two independent siRNAs significantly inhibits intramuscular adipocytes lipid accumulation and upregulates preadipocytes marker- preadipocyte factor 1 (pref1) expression. Consistently, siRNA treatments robustly decrease mRNA level of adipogenic related genes, including CCAAT enhancer binding protein alpha (Cebpα), Peroxisome proliferator activated receptor gamma (Pparg), Sterol regulatory element binding protein isoform 1c (Srebp1c), Fatty acids binding protein (aP2) and Lipoprotein lipase (Lpl). Next, adenovirus overexpression of LXRα does not affect intramuscular adipocytes adipogenesis manifested by Oil Red O signal measurement and adipogenic specific genes detection. Mechanically, we found that both CCAAT enhancer binding protein beta (Cebpβ) and Kruppel like factor 8 (Klf8) are potential targets of LXRα, indicated by having putative binding sites of LXRα at the promoter of these genes and similar expression pattern during adipogenesis comparing to LXRα. Importantly, mRNA levels of Cebpβ and Klf8 are downregulated significantly in goat LXRα knockdown intramuscular adipocyte. These results demonstrate that loss function of LXRα inhibits intramuscular adipogenesis possibly through down-regulation of Cebpβ and Klf8. Our research will provide new insights into mechanical regulation of goat IMF deposition.

scholarly journals CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice.

1997 ◽  
Vol 17 (12) ◽  
pp. 7353-7361 ◽  
Author(s):  
N A Timchenko ◽  
T E Harris ◽  
M Wilde ◽  
T A Bilyeu ◽  
B L Burgess-Beusse ◽  
...  
Keyword(s):  
Binding Protein ◽  
Hepatocyte Proliferation ◽  
Postnatal Life ◽  
Wild Type ◽  
Newborn Mice ◽  
P21 Protein ◽  
Protein Levels ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
P21 Proteins

CCAAT/enhancer binding protein alpha (C/EBP alpha) is expressed at high levels in quiescent hepatocytes and in differentiated adipocytes. In cultured cells, C/EBP alpha inhibits cell proliferation in part via stabilization of the p21 protein. The role of C/EBP alpha in regulating hepatocyte proliferation in vivo is presented herein. In C/EBP alpha knockout newborn mice, p21 protein levels are reduced in the liver, and the fraction of hepatocytes synthesizing DNA is increased. Greater than 30% of the hepatocytes in C/EBP alpha knockout animals continue to proliferate at day 17 of postnatal life when cell division in wild-type littermates is low (3%). p21 protein levels are relatively high in wild-type neonates but undetectable in C/EBP alpha knockout mice. The reduction of p21 protein in the highly proliferating livers that lack C/EBP alpha suggests that p21 is responsible for C/EBP alpha-mediated control of liver proliferation in newborn mice. During rat liver regeneration, the amounts of both C/EBP alpha and p21 proteins are decreased before DNA synthesis (6 to 12 h) and then return to presurgery levels at 48 h. Although C/EBP alpha controls p21 protein levels, p21 mRNA is not influenced by C/EBP alpha in liver. Using coimmunoprecipitation and a mammalian two-hybrid assay system, we have shown the interaction of C/EBP alpha and p21 proteins. Study of p21 stability in liver nuclear extracts showed that C/EBP alpha blocks proteolytic degradation of p21. Our data demonstrate that C/EBP alpha regulates hepatocyte proliferation in newborn mice and that in liver, the level of p21 protein is under posttranscriptional control, consistent with the hypothesis that protein-protein interaction with C/EBP alpha determines p21 levels.

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