Corticosteroid-binding globulin(CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone.Others and we have reported non-synonymous single nucleotide polymorphisms(SNPs) that influence C...Corticosteroid-binding globulin(CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone.Others and we have reported non-synonymous single nucleotide polymorphisms(SNPs) that influence CBG production or steroid-binding activity.However,no promoter polymorphisms affecting the transcription of human CBG gene(Cbg) have been reported.In the present study we investigated function implications of six promoter SNPs,including 26 C/G,54 C/T,144 G/C,161 A/G,205 C/A,and 443/444 AG/,five of which are located within the first 205 base pairs of 5'-flanking region and close to the highly conserved footprinted elements,TATA-box,or CCAAT-box.Luciferase reporter assays demonstrated that basal activity of the promoter carrying 54 T or 161 G was significantly enhanced.The first three polymorphisms,26 C/G,54 C/T,and 144 G/C located close to the putative hepatic nuclear factor(HNF) 1 binding elements,altered the transactivation effect of HNF1.We also found a negative promoter response to dexamethasone-activated glucocorticoid receptor(GR),although none of the SNPs affected its transrepression function.Our results suggest that human Cbg 26 C/G,54 C/T,144 G/C,and 161 A/G promoter polymorphisms alter transcriptional activity,and further studies are awaited to explore their association with physiological and pathological conditions.展开更多
Severe environmental conditions affect organisms in two major ways. The environment may be predictably severe such as in deserts, polar and alpine regions, or individuals may be exposed to temporarily extreme conditio...Severe environmental conditions affect organisms in two major ways. The environment may be predictably severe such as in deserts, polar and alpine regions, or individuals may be exposed to temporarily extreme conditions through weather, presence of predators, lack of food, social status etc. Existence in an extreme environment may be possible, but then to breed or molt in addition can present major bottlenecks that have resulted in the evolution of hormone-behavior adaptations to cope with unpredictable events. Examples of hormone-behavior adaptations in extreme conditions include attenuated testosterone secretion because territoriality and excess courtship may be too costly when there is one opportunity to reproduce. The individual may even become insensitive to testosterone when target areas of the brain regulating reproductive behavior no longer respond to the hormone. A second example is reduced sensitivity to glucocorticoids following acute stress during the breeding season or molt that allows successful reproduction and/or a vital renewal of the integument to endure extreme conditions during the rest of the year. Reduced sensitivity could involve： （a） modulated response of the hypothalamo-pituitary-adrenal axis, （b） reduced sensitivity to high glucocorticoid levels, or （c） a combination of （a） and （b）. Moreover, corticosteroid binding proteins （CBP） buffer responses to stress by reducing the movement of glucocorticoids into target cells. Finally, intracellular enzymes （11 β-hydroxysteroid dehydrogenase and variants） can deactivate glucocorticoids entering cells thus reducing interaction with receptors. These mechanisms have important implications for climate change and increasing extremes of weather [Current Zoology 57 （3）： 363-374, 2011].展开更多
基金supported by the National Basic Research Program of China (Grant No. 2011CB944403)the Knowledge Innovation Program of Chinese Academy of Sciences (GrantNo. KSCX3-IOZ-1005)
文摘Corticosteroid-binding globulin(CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone.Others and we have reported non-synonymous single nucleotide polymorphisms(SNPs) that influence CBG production or steroid-binding activity.However,no promoter polymorphisms affecting the transcription of human CBG gene(Cbg) have been reported.In the present study we investigated function implications of six promoter SNPs,including 26 C/G,54 C/T,144 G/C,161 A/G,205 C/A,and 443/444 AG/,five of which are located within the first 205 base pairs of 5'-flanking region and close to the highly conserved footprinted elements,TATA-box,or CCAAT-box.Luciferase reporter assays demonstrated that basal activity of the promoter carrying 54 T or 161 G was significantly enhanced.The first three polymorphisms,26 C/G,54 C/T,and 144 G/C located close to the putative hepatic nuclear factor(HNF) 1 binding elements,altered the transactivation effect of HNF1.We also found a negative promoter response to dexamethasone-activated glucocorticoid receptor(GR),although none of the SNPs affected its transrepression function.Our results suggest that human Cbg 26 C/G,54 C/T,144 G/C,and 161 A/G promoter polymorphisms alter transcriptional activity,and further studies are awaited to explore their association with physiological and pathological conditions.
基金JCW is grateful for grant number IOS-0750540 from the National Science Foundation and for support from the Endowed Professorship in Physiology, University of California, Davis. F.A. was supported by a Marie Curie Postdoctoral Fellowship （PolarClimStress） from the European Science Foundation. Current address for EA. is： Centre d＇Etudes Biologiques de Chize＇, CNRS, Villiers en Bois 79360, France.
文摘Severe environmental conditions affect organisms in two major ways. The environment may be predictably severe such as in deserts, polar and alpine regions, or individuals may be exposed to temporarily extreme conditions through weather, presence of predators, lack of food, social status etc. Existence in an extreme environment may be possible, but then to breed or molt in addition can present major bottlenecks that have resulted in the evolution of hormone-behavior adaptations to cope with unpredictable events. Examples of hormone-behavior adaptations in extreme conditions include attenuated testosterone secretion because territoriality and excess courtship may be too costly when there is one opportunity to reproduce. The individual may even become insensitive to testosterone when target areas of the brain regulating reproductive behavior no longer respond to the hormone. A second example is reduced sensitivity to glucocorticoids following acute stress during the breeding season or molt that allows successful reproduction and/or a vital renewal of the integument to endure extreme conditions during the rest of the year. Reduced sensitivity could involve： （a） modulated response of the hypothalamo-pituitary-adrenal axis, （b） reduced sensitivity to high glucocorticoid levels, or （c） a combination of （a） and （b）. Moreover, corticosteroid binding proteins （CBP） buffer responses to stress by reducing the movement of glucocorticoids into target cells. Finally, intracellular enzymes （11 β-hydroxysteroid dehydrogenase and variants） can deactivate glucocorticoids entering cells thus reducing interaction with receptors. These mechanisms have important implications for climate change and increasing extremes of weather [Current Zoology 57 （3）： 363-374, 2011].
