Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development.

Panduro, Arturo; Shalaby, Fouad; Shafritz, David A.

doi:10.1101/gad.1.10.1172

Cited by 100 publications

(69 citation statements)

References 58 publications

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“…In parallel, expression of AFP, a well known liver-specific developmentally regulated gene, was studied. AFP transcripts were highly expressed in fetal and perinatal liver and abruptly shut off after 15 days, in accordance to previous studies (28). These observations, along with our previous analysis of HEPC expression (7), suggested that this gene is liver-specific and its expression is related to the fully differentiated hepatocyte.…”

Section: Hepc Gene Expression Is Regulated During Rat Liver Developmesupporting

confidence: 78%

C/EBPα Regulates Hepatic Transcription of Hepcidin, an Antimicrobial Peptide and Regulator of Iron Metabolism

Courselaud

Pigeon

Inoue

et al. 2002

Journal of Biological Chemistry

226

177

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Originally identified as a gene up-regulated by iron overload in mouse liver, the HEPC gene encodes hepcidin, the first mammalian liver-specific antimicrobial peptide and potential key regulator of iron metabolism. Here we demonstrate that during rat liver development, amounts of HEPC transcripts were very low in fetal liver, strongly and transiently increased shortly after birth, and reappeared in adult liver. To gain insight into mechanisms that regulate hepatic expression of hepcidin, 5-flanking regions of human and mouse HEPC genes were isolated and analyzed by functional and DNA binding assays. Human and mouse HEPC promoterluciferase reporter vectors exhibited strong basal activity in hepatoma HuH-7 and mouse hepatocytes, respectively, but not in non-hepatic U-2OS cells. We found that CCAAT/enhancer-binding protein ␣ (C/EBP␣) and C/EBP␤ were respectively very potent and weak activators of both human and mouse promoters. In contrast, co-expression of hepatocyte nuclear factor 4␣ (HNF4␣) failed to induce HEPC promoter activity. By electrophoretic mobility shift assay we demonstrated that one putative C/EBP element found in the human HEPC promoter (؊250/؊230) predominantly bound C/EBP␣ from rat liver nuclear extracts. Hepatic deletion of the C/EBP␣ gene resulted in reduced expression of HEPC transcripts in mouse liver. In contrast, amounts of HEPC transcripts increased in liver-specific HNF4␣-null mice. Decrease of hepcidin mRNA in mice lacking hepatic C/EBP␣ was accompanied by iron accumulation in periportal hepatocytes. Finally, iron overload led to a significant increase of C/EBP␣ protein and HEPC transcripts in mouse liver. Taken together, these data demonstrate that C/EBP␣ is likely to be a key regulator of HEPC gene transcription and provide a novel mechanism for cross-talk between the C/EBP pathway and iron metabolism.

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Section: Hepc Gene Expression Is Regulated During Rat Liver Developmesupporting

confidence: 78%

C/EBPα Regulates Hepatic Transcription of Hepcidin, an Antimicrobial Peptide and Regulator of Iron Metabolism

Courselaud

Pigeon

Inoue

et al. 2002

Journal of Biological Chemistry

226

177

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“…The main goal ofthis study was (21,27). Such a behavior of these two transcriptionally regulated genes may indicate a coordinate regulation at the molecular level, possibly due to structural homologies in the enhancer/promoter regions responsive to specific nuclear transcriptional factors.…”

Section: Discussionmentioning

confidence: 99%

Albumin gene expression is down-regulated by albumin or macromolecule infusion in the rat.

Pietrangelo¹,

Panduro²,

Chowdhury³

et al. 1992

J. Clin. Invest.

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IntroductionA novel feedback regulatory mechanism operating on transcription of the albumin gene is described in the rat. In 1946, it was proposed that circulating colloids, including serum albumin, may affect the synthesis and/or secretion ofalbumin in the liver. The molecular basis for this proposed regulation has now been investigated by adding oncotically active macromolecules to the circulation of normal or genetically albumin-deficient Nagase analbuminemic rats (NAR) and analyzing the hepatic expression of genes, including albumin after 24 h. The transcription rate of the albumin gene was higher in NAR than in normal rats and was dramatically reduced by raising serum albumin to 1.6 g/dl. Intravenous infusion of albumin into normal rats also decreased transcriptional activity of the albumin gene by 50-60%, and this decrease correlated with changes in serum colloid osmotic pressure after albumin infusion. Inhibition ofalbumin gene transcription was also observed upon intravenous infusion of other protein or nonprotein macromolecules, such as y-globulin and dextran. This down-regulation appears to control the steady-state level of albumin mRNA in the liver.Aside from a concomitant decrease in apo E gene transcription after albumin or macromolecule infusion, there was no change in the transcription rate of other genes, including those exhibiting liver-preferred or -specific expression (e.g., tyrosine aminotransferase, cytochrome P450, a1-antitrypsin, apolipoproteins A-I and B, and transferrin) or general cellular expression (e.g., a-tubulin, pro a2 collagen, and fl-actin). The liver represents the main source of serum albumin (1, 2). Normally, the plasma albumin concentration remains constant at 3.5-4.0 g/dl, suggesting an active regulation ofalbumin metabolism. Several pathophysiological studies have shown that hormones, malnutrition, and stress may influence albumin synthesis (3-7); however, little is known about the "physiological" regulator(s) of albumin or other proteins synthesized by the liver. Many years ago, Biorneboe (8, 9) observed that an increase in the serum concentration ofglobulins is followed by a concomitant decrease ofserum albumin in hepatitis and after immunization, and he proposed that the serum colloid osmotic pressure (COP)' might serve as a regulator for changes in serum protein concentration. In support ofthis hypothesis, hyperglobulinemia, infusion of y-globulin, and administration of dextran were also shown to decrease serum albumin levels (10-12). Moreover, in a variety ofconditions in which serum albumin levels fall either acutely (e.g., plasmapheresis) or chronically (e.g., nephrotic syndrome), hepatic albumin synthesis is increased (13)(14)(15).In the 1960's, Rothschild et al. (16) demonstrated that addition of albumin to the perfusate medium ofthe isolated rabbit liver decreases incorporation of labeled amino acids into albumin. Other studies extended this observation to macromolecules other than albumin, and it was proposed that all these agents may work through a com...

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“…This gene is expressed mainly in liver cells, where early in fetal development it is coactivated along with the closely linked and evolutionarily related a-fetoprotein (AFP) gene. After birth, AFP expression ceases rapidly, whereas albumin synthesis increases to become the major serum protein synthesized and secreted by adult hepatocytes (Panduro et al 1987, see references therein).…”

mentioning

confidence: 99%

A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells.

Cereghini¹,

Blumenfeld²,

Yaniv³

1988

Genes Dev.

303

235

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We have identified and characterized two mutually exclusive nuclear proteins that interact with a single crucial element of the albumin promoter. One, albumin proximal factor (APF), is found only in liver or differentiated hepatoma cells and is probably identical to the liver-specific factors named HNFl, alTFB, or HPl-binding protein. The other, variant albumin proximal factor (vAPF), is present in dedifferentiated hepatoma cells as well as in somatic cell hybrids that show extinction of the expression of liver-specific proteins, including albumin. Reversion to the hepatic phenotype of either a dedifferentiated variant or an extinguished somatic hybrid clone is accompanied by loss of vAPF and reappearance of APF. These two proteins differ in their thermostability and in their molecular weight, while displaying identical sequence specificities. Both proteins interact with a homologous motif present in promoter regions of several other liver-specific genes. In vitro transcription assays, using a rat liver nuclear extract, indicate that the binding of APF to its target sequence is required for albumin transcription. These results suggest that a modification in the primary structure of a transcription factor is correlated with the differentiated state of the hepatic cell.

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Changing patterns of transcriptional and post-transcriptional control of liver-specific gene expression during rat development.

Cited by 100 publications

References 58 publications

C/EBPα Regulates Hepatic Transcription of Hepcidin, an Antimicrobial Peptide and Regulator of Iron Metabolism

C/EBPα Regulates Hepatic Transcription of Hepcidin, an Antimicrobial Peptide and Regulator of Iron Metabolism

Albumin gene expression is down-regulated by albumin or macromolecule infusion in the rat.

A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells.

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