Transcriptional and posttranscriptional regulation of hepatic β₂‐adrenergic receptor gene expression during development

Abstract

Hepatic responsiveness to beta 2-adrenergic stimulation is dynamically regulated during early development as well as following hepatic injury and disease. In the present study, the molecular mechanisms that underlie the decline in the steady-state levels of hepatic beta 2-adrenergic receptor mRNA that occurs during development in the male rat were investigated. As determined by nuclear run-on assays, an age-associated reduction in beta 2-adrenergic receptor gene transcription was observed. The transcription rate of the beta 2-adrenergic receptor gene in postnatal day 18 liver was approximately 50% lower than that of fetal liver. Stability of beta 2-adrenergic receptor gene transcripts was highest (t1/2 approximately 6h) in hepatocytes isolated from fetal rats and was lowest (t1/2 approximately 6h) in hepatocytes from postnatal day 14 rats. In fetal hepatocytes, but not postnatal day 2 hepatocytes, cycloheximide appeared to stabilize beta 2-adrenergic receptor gene transcripts in the presence of actinomycin D. These findings establish the molecular basis of reduced steady-state levels of beta 2-adrenergic receptor mRNA in liver during early postnatal development and suggest multilevel regulatory control of hepatic beta 2-adrenergic receptor gene expression.

DNA Elements and Protein Factors Involved in the Transcription of the β2-Adrenergic Receptor Gene in Rat Liver. The Negative Regulatory Role of C/EBPα

“…Northern Analysis of β 2 AR mRNA. Previous Northern blot analyses of β 2 AR transcripts indicated a major hybridizing band ranging in size from 2.0 kb in rat liver (Baeyens & Cornett, 1993) and DDT 1 MF-2 cells (Collins et al, 1988) to 2.2 kb in mouse lymphoma cells (Bahouth et al, 1988), or 2.1 kb in rat lung and prostate (Frielle et al, 1987). In some studies, a minor band of 1.6-1.8 kb was also detected (Collins et al, 1988).…”

“…The expression of the β 2 AR gene is high in the fetal rat liver, but declines rapidly during ontogenic development (Baeyens & Cornett, 1993). Thus, this gene appears to belong to the group of developmentally regulated genes which are under the control of multiple promoters (Schibler & Sierra, 1987).…”

“…The expression of C/EBPR is high in terminally differentiated hepatocytes, but low in dedifferentiated liver tissue, such as in fetal liver (Birkenmeier et al, 1989), in liver tumor cells (Friedman et al, 1989), in primary cultured hepatocytes (Mischoulon et al, 1992), and in the regenerating liver (see above). In contrast, β 2 AR activation inhibits glycogen synthase and leads to glycogen breakdown, and β 2 AR expression is very low in the differentiated, adult rat liver, but high in fetal liver (Blair et al, 1979;Baeyens & Cornett, 1993), in liver tumors (Bevilacqua et al, 1991), in primary cultured hepatocytes (Nakamura et al, 1983;Refsnes et al, 1983), and in the regenerating liver (see above). This striking, inverse relationship makes it very likely that C/EBPR is a negative regulator of hepatic β 2 AR expression in the rat in vivo.…”

Age and region‐dependent contraction to α‐adrenoceptor agonists in rat and guinea‐pig isolated trachea

“…However, a study examining the expression of α‐adrenoceptor genes in the superior cervical ganglion demonstrated a significant fall with maturation in the expression of the α 1b ‐adrenoceptor subtype, but no change in the expression of the α‐ 1c ‐ or α 2 ‐adrenoceptor subtype transcripts (Vidovic & Hill, 1997). The transcription rate of rat hepatic β 2 ‐adrenoceptors is also significantly reduced in postnatal, compared to foetal animals (Baeyens & Cornett, 1993). These studies provide evidence that changes may occur in adrenoceptor expression with respect to animal age during the maturation phase of growth.…”

Regulation of β-Adrenergic receptor responsiveness modulation of receptor gene expression

“…~IAR transcripts vary between 2.5 kb and 3.0 kb in length (Frielle et al 1987;Feve et al 1990;Machida et al 1990;Cohen et al 1993;Evanko et al 1998), for the ~2AR two mRNA species have been detected -a major one ranging between 2.0 kb and 2.2 kb in size and a minor one between 1.6 kb and 1.8 kb (Emorine et al 1987;Collins et al 1988Collins et al , 1989Baeyens and Cornett, 1993;Jiang et al 1996). ~3AR transcripts between 2.1 kb and 2.8 kb have been found in several human and rodent tissues (Emorine et al 1989;van Spronsen et al 1993;Kriefet al 1993;Granneman and Lahners, 1994 Table 2) some human organs larger mRNA species were also visible (Emorine et al 1989).…”