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Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.

Mice carrying a hepatocyte-specific inactivation of the glucorticoid receptor (GR) gene show a dramatic reduction in body size. Growth hormone signaling mediated by the Stat5 transcription factors is impaired. We show that Stat5 proteins physically interact with GR and GR is present in vivo on Stat5-dependent IGF-I and ALS regulatory regions. Interestingly, mice with a DNA-binding-deficient GR but an unaltered ability to interact with STAT5 (GR dim/dim ) have a normal body size and normal levels of Stat5-dependent mRNAs. These findings strongly support the model in which GR acts as a coactivator for Stat5-dependent transcription upon GH stimulation and reveal an essential role of hepatic GR in the control of body growth. Received September 8, 2003; revised version accepted January 27, 2004. Glucocorticoids (GCs), which are synthesized in the adrenal cortex, act in many if not all cells of the body and play important roles in development and homeostasis. The effects of the hormone are mediated by the glucocorticoid receptor (GR) that is ubiquitously expressed and by the mineralocorticoid receptor that displays a more restricted expression profile. GR activity depends on the binding of its ligand, which is released on physiological, circadian, and stress stimuli, and thus GR participates in coordinating the organism's responses to the environment. GR can both activate and repress transcription of target genes via DNA binding to glucocorticoid responsive elements (GREs) or cross-talk with other transcription factors (Beato et al. 1995;Tronche et al. 1998). Because the liver is a major target organ for GCs in control of glycogen metabolism and gluconeogenesis, we wished to address the function of hepatic GR by genetic means. As shown previously, loss of the receptor leads to lethality (Cole et al. 1995;Tronche et al. 1998). We therefore have generated cell/tissue-specific and functionselective mutations using the Cre/loxP system Tronche et al. 1999). To define the role of GR in hepatocytes, we expressed the recombinase in hepatocytes under the control of the albumin promoter and the albumin and ␣-fetoprotein enhancers to generate mutant mice with selective inactivation of GR in these cells only (GR AlfpCre mice; Kellendonk et al. 2000). This approach allowed us to partially circumvent the perinatal lethality of GR null mutants. Surprisingly, adult mice with the hepatocyte-specific loss of GR have a severe reduction in body weight. Analysis of these mice revealed not only a novel function of GR in growth control, but also an unprecedented mode of activity. Results and DiscussionApproximately 50% of the homozygous mutants died within 48 h after birth, likely due to the metabolic consequences of the hepatocyte-specific GR knock-out (data not shown). No increase in mortality was observed at later stages. Mice lacking GR in hepatocytes were indistinguishable from their littermates until 3-4 wk of age, but later displayed a severe growth deficit that was more pronounced in adult males than in females (reduction by 32%...

Summary:We have studied 27 triads of mother, daughter and grandmother for possible genetic influence on distal and proximal forearm bone density, measured by single photon absorptiometry.We found a significant correlation of bone density at the proximal forearm between the mothers and grandmothers (r = 0.499, P < 0.01). There was also a weak correlation between proximal forearm bone densities of mothers and daughters (r = 0.327, P < 0.1).Significant correlations were found between the three generations for grip strength, pedometry, height and triceps skinfold thickness. There was also significant correlation between mother and grandmother for alcohol intake. There was no correlation for contraceptive pill use, smoking, dietary calcium intake, body weight or body mass index.The study concludes that, although there are similarities in bone mineral content between the three generations, genetic factors cannot be conclusively proven to be the major determinant of bone density. Lifestyle and environmental factors may have a bearing on achieving the peak bone mass and subsequent development of osteoporosis.

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