Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cy... more Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cyclase structurally, molecularly, and biochemically distinct from the G protein-regulated, transmembrane adenylyl cyclases (tmACs). sAC possesses no transmembrane domains and is insensitive to classic modulators of tmACs, such as heterotrimeric G proteins and P site ligands. Thus, sAC defines an independently regulated cAMP signaling system within mammalian cells.
Page 1. Anhydroretlnol: A Naturally Occurring Inhibitor of Lymphocyte Physiology By Jochen Buck,~... more Page 1. Anhydroretlnol: A Naturally Occurring Inhibitor of Lymphocyte Physiology By Jochen Buck,~ Felix Griin, Fadila Derguini,$ Yq Chen,~ Shoji Kimura, Noa Noy,* and Ulrich H~immerling ... 7sooo~ and SF 9 from Dr. Philip W. Majerus (Washington University, B St. Louis, MO). ...
evidence in the literature (reviewed in references 4 and 5) that retinoids influence immune respo... more evidence in the literature (reviewed in references 4 and 5) that retinoids influence immune responses, to our knowledge systematic studies to uncover the mechanism underlying immune system enhancement have not been carried out . In the course of studies of a growth factor for human, EBVtransformed B lym- phocytes, we have isolated a lipid-like molecule by extraction ofserum with organic
Currently, there is no way to predict with a high degree of sensitivity and specificity which pat... more Currently, there is no way to predict with a high degree of sensitivity and specificity which patients are likely to develop systemic inflammatory response syndrome (SIRS) following systemic infection, trauma, organ rejection, or blood loss. The level of human lipopolysaccharide-binding protein (LBP) was determined in the plasma of 22 patients with a clinical diagnosis of early SIRS. Twenty-nine plasma samples
Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cy... more Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cyclase structurally, molecularly, and biochemically distinct from the G protein-regulated, transmembrane adenylyl cyclases (tmACs). sAC possesses no transmembrane domains and is insensitive to classic modulators of tmACs, such as heterotrimeric G proteins and P site ligands. Thus, sAC defines an independently regulated cAMP signaling system within mammalian cells.
The Journal of experimental medicine, Jan 22, 2015
CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals duri... more CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals during this process remains unknown. We show that during TEM, endothelial cell (EC) CD99 activates protein kinase A (PKA) via a signaling complex formed with the lysine-rich juxtamembrane cytoplasmic tail of CD99, the A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC). PKA then stimulates membrane trafficking from the lateral border recycling compartment to sites of TEM, facilitating the passage of leukocytes across the endothelium. Pharmacologic or genetic inhibition of EC sAC or PKA, like CD99 blockade, arrests neutrophils and monocytes partway through EC junctions, in vitro and in vivo, without affecting leukocyte adhesion or the expression of relevant cellular adhesion molecules. This is the first description of the CD99 signaling pathway in TEM as well as the first demonstration of a role for sAC in leukocyte TEM.
... 8 j. Kawabe, Y. Toya, C. Schwencke, N. Oka, T. Ebina, and Y. lshakawa, J ... separation by fi... more ... 8 j. Kawabe, Y. Toya, C. Schwencke, N. Oka, T. Ebina, and Y. lshakawa, J ... separation by filtering through blotting paper VWR 238 (Ahlstrom Filtration, Mount Holly Springs, PA). ... of 50 testes each) over diethylaminoethyl (DE-52) cellulose anion-exchange columns, a weak anion ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014
Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in subst... more Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in substrate availability and bioenergetic demands by employing rapid, short-term, metabolic adaptation mechanisms, such as phosphorylation-dependent protein regulation. In mammalian cells, an intramitochondrial CO2-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway regulates aerobic energy production. One target of this pathway involves phosphorylation of cytochrome c oxidase (COX) subunit 4-isoform 1 (COX4i1), which modulates COX allosteric regulation by ATP. However, the role of the CO2-sAC-cAMP-PKA signalosome in regulating COX activity and mitochondrial metabolism and its evolutionary conservation remain to be fully established. We show that in Saccharomyces cerevisiae, normoxic COX activity measured in the presence of ATP is 55% lower than in the presence of ADP. Moreover, the adenylyl cyclase Cyr1 activity is present in mitochondria, and it contributes to the ATP-media...
Cyclic AMP (cAMP) is an evolutionarily conserved regulator of metabolism. Recently, we identified... more Cyclic AMP (cAMP) is an evolutionarily conserved regulator of metabolism. Recently, we identified a novel mammalian source of cAMP - soluble adenylyl cyclase (sAC) - that is regulated directly by bicarbonate ions (HCO(3)(-)). As the concentration of HCO(3)(-) reflects cellular levels of carbon dioxide (CO(2)), energy-generating metabolic processes (which increase intracellular CO(2)) are poised to activate bicarbonate-responsive sAC. This direct link between metabolic activity, sAC and cAMP could represent an evolutionarily conserved mechanism of metabolic feedback regulation.
Proceedings of the National Academy of Sciences, 1997
Murine 3T3 cells arrest in a quiescent, nondividing state when transferred into medium containing... more Murine 3T3 cells arrest in a quiescent, nondividing state when transferred into medium containing little or no serum. Within the first day after transfer, fibroblasts can be activated to proliferate by platelet-derived growth factor (PDGF) alone; cells starved longer than 1 day, however, are activated only by serum. We demonstrate that endogenous vitamin A (retinol) or retinol supplied by serum prevents cell death and that retinol, in combination with PDGF, can fully replace serum in activating cells starved longer than 1 day. The physiological retinol derivative 14-hydroxy-4, 14-retro-retinol, but not retinoic acid, can replace retinol in rescuing or activating 3T3 cells. Anhydroretinol, another physiological retinol metabolite that acts as a competitive antagonist of retinol, blocks cell activation by serum, indicating that retinol is a necessary component of serum. It previously has been proposed that activation of 3T3 cells requires two factors in serum, an activation factor shown to be PDGF and an unidentified survival factor. We report that retinol is the survival factor in serum.
Proceedings of the National Academy of Sciences, 1996
Retinoids are a large family of natural and synthetic compounds related to vitamin A that have pl... more Retinoids are a large family of natural and synthetic compounds related to vitamin A that have pleiotropic effects on body physiology, reproduction, immunity, and embryonic development. The diverse activities of retinoids are primarily mediated by two families of nuclear retinoic acid receptors, the RARs and RXRs. Retinoic acids are thought to be the only natural ligands for these receptors and are widely assumed to be the active principle of vitamin A. However, during an unbiased, bioactivity-guided fractionation of Xenopus embryos, we were unable to detect significant levels of all-trans or 9-cis retinoic acids. Instead, we found that the major bioactive retinoid in the Xenopus egg and early embryo is 4-oxoretinaldehyde, which is capable of binding to and transactivating RARs. In addition to its inherent activity, 4-oxoretinaldehyde appears to be a metabolic precursor of two other RAR ligands, 4-oxoretinoic acid and 4-oxoretinol. The remarkable increase in activity of retinaldehyde and retinol as a consequence of 4-oxo derivatization suggests that this metabolic step could serve a critical regulatory function during embryogenesis.
Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cy... more Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cyclase structurally, molecularly, and biochemically distinct from the G protein-regulated, transmembrane adenylyl cyclases (tmACs). sAC possesses no transmembrane domains and is insensitive to classic modulators of tmACs, such as heterotrimeric G proteins and P site ligands. Thus, sAC defines an independently regulated cAMP signaling system within mammalian cells.
Page 1. Anhydroretlnol: A Naturally Occurring Inhibitor of Lymphocyte Physiology By Jochen Buck,~... more Page 1. Anhydroretlnol: A Naturally Occurring Inhibitor of Lymphocyte Physiology By Jochen Buck,~ Felix Griin, Fadila Derguini,$ Yq Chen,~ Shoji Kimura, Noa Noy,* and Ulrich H~immerling ... 7sooo~ and SF 9 from Dr. Philip W. Majerus (Washington University, B St. Louis, MO). ...
evidence in the literature (reviewed in references 4 and 5) that retinoids influence immune respo... more evidence in the literature (reviewed in references 4 and 5) that retinoids influence immune responses, to our knowledge systematic studies to uncover the mechanism underlying immune system enhancement have not been carried out . In the course of studies of a growth factor for human, EBVtransformed B lym- phocytes, we have isolated a lipid-like molecule by extraction ofserum with organic
Currently, there is no way to predict with a high degree of sensitivity and specificity which pat... more Currently, there is no way to predict with a high degree of sensitivity and specificity which patients are likely to develop systemic inflammatory response syndrome (SIRS) following systemic infection, trauma, organ rejection, or blood loss. The level of human lipopolysaccharide-binding protein (LBP) was determined in the plasma of 22 patients with a clinical diagnosis of early SIRS. Twenty-nine plasma samples
Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cy... more Summary 'Soluble adenylyl cyclase' (sAC) represents a novel form of mammalian adenylyl cyclase structurally, molecularly, and biochemically distinct from the G protein-regulated, transmembrane adenylyl cyclases (tmACs). sAC possesses no transmembrane domains and is insensitive to classic modulators of tmACs, such as heterotrimeric G proteins and P site ligands. Thus, sAC defines an independently regulated cAMP signaling system within mammalian cells.
The Journal of experimental medicine, Jan 22, 2015
CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals duri... more CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals during this process remains unknown. We show that during TEM, endothelial cell (EC) CD99 activates protein kinase A (PKA) via a signaling complex formed with the lysine-rich juxtamembrane cytoplasmic tail of CD99, the A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC). PKA then stimulates membrane trafficking from the lateral border recycling compartment to sites of TEM, facilitating the passage of leukocytes across the endothelium. Pharmacologic or genetic inhibition of EC sAC or PKA, like CD99 blockade, arrests neutrophils and monocytes partway through EC junctions, in vitro and in vivo, without affecting leukocyte adhesion or the expression of relevant cellular adhesion molecules. This is the first description of the CD99 signaling pathway in TEM as well as the first demonstration of a role for sAC in leukocyte TEM.
... 8 j. Kawabe, Y. Toya, C. Schwencke, N. Oka, T. Ebina, and Y. lshakawa, J ... separation by fi... more ... 8 j. Kawabe, Y. Toya, C. Schwencke, N. Oka, T. Ebina, and Y. lshakawa, J ... separation by filtering through blotting paper VWR 238 (Ahlstrom Filtration, Mount Holly Springs, PA). ... of 50 testes each) over diethylaminoethyl (DE-52) cellulose anion-exchange columns, a weak anion ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014
Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in subst... more Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in substrate availability and bioenergetic demands by employing rapid, short-term, metabolic adaptation mechanisms, such as phosphorylation-dependent protein regulation. In mammalian cells, an intramitochondrial CO2-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway regulates aerobic energy production. One target of this pathway involves phosphorylation of cytochrome c oxidase (COX) subunit 4-isoform 1 (COX4i1), which modulates COX allosteric regulation by ATP. However, the role of the CO2-sAC-cAMP-PKA signalosome in regulating COX activity and mitochondrial metabolism and its evolutionary conservation remain to be fully established. We show that in Saccharomyces cerevisiae, normoxic COX activity measured in the presence of ATP is 55% lower than in the presence of ADP. Moreover, the adenylyl cyclase Cyr1 activity is present in mitochondria, and it contributes to the ATP-media...
Cyclic AMP (cAMP) is an evolutionarily conserved regulator of metabolism. Recently, we identified... more Cyclic AMP (cAMP) is an evolutionarily conserved regulator of metabolism. Recently, we identified a novel mammalian source of cAMP - soluble adenylyl cyclase (sAC) - that is regulated directly by bicarbonate ions (HCO(3)(-)). As the concentration of HCO(3)(-) reflects cellular levels of carbon dioxide (CO(2)), energy-generating metabolic processes (which increase intracellular CO(2)) are poised to activate bicarbonate-responsive sAC. This direct link between metabolic activity, sAC and cAMP could represent an evolutionarily conserved mechanism of metabolic feedback regulation.
Proceedings of the National Academy of Sciences, 1997
Murine 3T3 cells arrest in a quiescent, nondividing state when transferred into medium containing... more Murine 3T3 cells arrest in a quiescent, nondividing state when transferred into medium containing little or no serum. Within the first day after transfer, fibroblasts can be activated to proliferate by platelet-derived growth factor (PDGF) alone; cells starved longer than 1 day, however, are activated only by serum. We demonstrate that endogenous vitamin A (retinol) or retinol supplied by serum prevents cell death and that retinol, in combination with PDGF, can fully replace serum in activating cells starved longer than 1 day. The physiological retinol derivative 14-hydroxy-4, 14-retro-retinol, but not retinoic acid, can replace retinol in rescuing or activating 3T3 cells. Anhydroretinol, another physiological retinol metabolite that acts as a competitive antagonist of retinol, blocks cell activation by serum, indicating that retinol is a necessary component of serum. It previously has been proposed that activation of 3T3 cells requires two factors in serum, an activation factor shown to be PDGF and an unidentified survival factor. We report that retinol is the survival factor in serum.
Proceedings of the National Academy of Sciences, 1996
Retinoids are a large family of natural and synthetic compounds related to vitamin A that have pl... more Retinoids are a large family of natural and synthetic compounds related to vitamin A that have pleiotropic effects on body physiology, reproduction, immunity, and embryonic development. The diverse activities of retinoids are primarily mediated by two families of nuclear retinoic acid receptors, the RARs and RXRs. Retinoic acids are thought to be the only natural ligands for these receptors and are widely assumed to be the active principle of vitamin A. However, during an unbiased, bioactivity-guided fractionation of Xenopus embryos, we were unable to detect significant levels of all-trans or 9-cis retinoic acids. Instead, we found that the major bioactive retinoid in the Xenopus egg and early embryo is 4-oxoretinaldehyde, which is capable of binding to and transactivating RARs. In addition to its inherent activity, 4-oxoretinaldehyde appears to be a metabolic precursor of two other RAR ligands, 4-oxoretinoic acid and 4-oxoretinol. The remarkable increase in activity of retinaldehyde and retinol as a consequence of 4-oxo derivatization suggests that this metabolic step could serve a critical regulatory function during embryogenesis.
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