Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons

Four ADR1c mutations that occur close to Ser-230 of the Saccharomyces cerevisiae transcriptional activator ADR1 and which greatly enhance the ability of ADR1 to activate ADH2 expression under glucose-repressed conditions have been shown to reduce or eliminate cyclic AMP-dependent protein kinase (cAPK) phosphorylation of Ser-230 in vitro. In addition, unregulated cAPK expression in vivo blocks ADH2 depression in an ADR1-dependent fashion in which ADR1c mutations display decreased sensitivity to unregulated cAPK activity. Taken together, these data have suggested that ADR1c mutations enhance ADR1 activity by blocking cAPK phosphorylation and inactivation of Ser-230. We have isolated and characterized an additional 17 ADR1c mutations, defining 10 different amino acid changes, that were located in the region defined by amino acids 227 through 239 of ADR1. Three observations, however, indicate that the ADR1c phenotype is not simply equivalent to a lack of cAPK phosphorylation. First, only some of these newly isolated ADR1c mutations affected the ability of yeast cAPK to phosphorylate corresponding synthetic peptides modeled on the 222 to 234 region of ADR1 in vitro. Second, we observed that strains lacking cAPK activity did not display enhanced ADH2 expression under glucose growth conditions. Third, when Ser-230 was mutated to a nonphosphorylatable residue, lack of cAPK activity led to a substantial increase in ADH2 expression under glucose-repressed conditions. Thus, while cAPK controls ADH2 expression and ADR1 is required for this control, cAPK acts by a mechanism that is independent of effects on ADR1 Ser-230. It was also observed that deletion of the ADR1c region resulted in an ADR1c phenotype. The ADR1c region is, therefore, involved in maintaining ADR1 in an inactive form. ADR1c mutations may block the binding of a repressor to ADR1 or alter the structure of ADR1 so that transcriptional activation regions become unmasked.

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Cyclic AMP-dependent protein kinase inhibits the activity of myogenic helix-loop-helix proteins.

Molecular and Cellular Biology ◽

10.1128/mcb.12.10.4478 ◽

1992 ◽

Vol 12 (10) ◽

pp. 4478-4485 ◽

Cited By ~ 68

Author(s):

L Li ◽

R Heller-Harrison ◽

M Czech ◽

E N Olson

Keyword(s):

Protein Kinase ◽

Cyclic Amp ◽

Transcriptional Activation ◽

Consensus Sequence ◽

Signal Transduction Pathway ◽

Specific Gene ◽

Dependent Protein Kinase ◽

Dependent Protein

Differentiation of skeletal muscle cells is inhibited by the cyclic AMP (cAMP) signal transduction pathway. Here we report that the catalytic subunit of cAMP-dependent protein kinase (PKA) can substitute for cAMP and suppress muscle-specific transcription by silencing the activity of the MyoD family of regulatory factors, which includes MyoD, myogenin, myf5, and MRF4. Repression by the PKA catalytic (C) subunit is directed at the consensus sequence CANNTG, the target for DNA binding and transcriptional activation by these myogenic regulators. Phosphopeptide mapping of myogenin in vitro and in vivo revealed two PKA phosphorylation sites, both within the basic region. However, repression of myogenin function by PKA does not require direct phosphorylation of these sites but instead involves an indirect mechanism with one or more intermediate steps. Regulation of the transcriptional activity of the MyoD family by modulation of the cAMP signaling pathway may account for the inhibitory effects of certain peptide growth factors on muscle-specific gene expression and may also determine the responsiveness of different cell types to myogenic conversion by these myogenic regulators.

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Parathyroid hormone induces rat interstitial collagenase mRNA through Ets-1 facilitated by cyclic AMP response element-binding protein and Ca(2+)/calmodulin-dependent protein kinase II in osteoblastic cells

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0250073 ◽

2000 ◽

Vol 25 (1) ◽

pp. 73-84 ◽

Cited By ~ 26

Author(s):

CO Quinn ◽

RA Rajakumar ◽

OA Agapova

Keyword(s):

Parathyroid Hormone ◽

Protein Kinase ◽

Cyclic Amp ◽

Osteoblastic Cells ◽

Dependent Protein Kinase ◽

Response Element ◽

Nuclear Factors ◽

Dependent Protein ◽

Cyclic Amp Response Element ◽

Interstitial Collagenase

Parathyroid hormone (PTH), a powerful bone-resorbing agent, is capable of stimulating interstitial collagenase (MMP-13) mRNA production in osteoblastic cells. In this study, a PEA3 consensus binding sequence (-80; AGGAAGT) in addition to a 'TRE-like' sequence (-89; CGACTCA) in the 5' upstream regulatory region of the rat MMP-13 gene were examined. In response to PTH, there was a time-dependent increase in binding of nuclear factors to an oligonucleotide containing the PEA3 region (-95 to -71). This increase in binding was first observed at 0.5 h, peaked at 4 h (7. 6-fold) then returned to basal levels by 24 h. Mutagenesis of the PEA3 site in a chloramphenicol acetyl transferase (CAT) construct containing 5' upstream regulatory sequence of the rat MMP-13 gene significantly decreased activation by PTH. PTH-mediated binding of nuclear factors to an oligonucleotide containing the mutant PEA3 sequence was decreased as compared with the wild type. Mutation or deletion of the TRE-like sequence affected basal as well as PTH-mediated induction of corresponding CAT constructs. Treatment with KN93, a Ca(2+)/calmodulin-dependent protein kinase II specific inhibitor, greatly reduced the amount of protein binding to the PEA3 region in response to PTH which correlated to a notable decrease in the amount of MMP-13 mRNA produced in response to PTH. Antibodies against Ets-1, cyclic AMP response element (CREB)-binding protein (CBP) and CREB were capable of supershifting proteins binding to the oligonucleotide containing the PEA3 region. These data suggest a possible co-operative interaction of factors binding to the PEA3 and TRE-like sequences and provide the first indication of a role for a calcium-mediated pathway in the PTH induction of MMP-13 mRNA in osteoblastic cells.

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Cyclic AMP-dependent protein kinase inhibits the activity of myogenic helix-loop-helix proteins

Molecular and Cellular Biology ◽

10.1128/mcb.12.10.4478-4485.1992 ◽

1992 ◽

Vol 12 (10) ◽

pp. 4478-4485

Author(s):

L Li ◽

R Heller-Harrison ◽

M Czech ◽

E N Olson

Keyword(s):

Protein Kinase ◽

Cyclic Amp ◽

Transcriptional Activation ◽

Consensus Sequence ◽

Signal Transduction Pathway ◽

Specific Gene ◽

Dependent Protein Kinase ◽

Dependent Protein

Differentiation of skeletal muscle cells is inhibited by the cyclic AMP (cAMP) signal transduction pathway. Here we report that the catalytic subunit of cAMP-dependent protein kinase (PKA) can substitute for cAMP and suppress muscle-specific transcription by silencing the activity of the MyoD family of regulatory factors, which includes MyoD, myogenin, myf5, and MRF4. Repression by the PKA catalytic (C) subunit is directed at the consensus sequence CANNTG, the target for DNA binding and transcriptional activation by these myogenic regulators. Phosphopeptide mapping of myogenin in vitro and in vivo revealed two PKA phosphorylation sites, both within the basic region. However, repression of myogenin function by PKA does not require direct phosphorylation of these sites but instead involves an indirect mechanism with one or more intermediate steps. Regulation of the transcriptional activity of the MyoD family by modulation of the cAMP signaling pathway may account for the inhibitory effects of certain peptide growth factors on muscle-specific gene expression and may also determine the responsiveness of different cell types to myogenic conversion by these myogenic regulators.

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ADR1c mutations enhance the ability of ADR1 to activate transcription by a mechanism that is independent of effects on cyclic AMP-dependent protein kinase phosphorylation of Ser-230.

Molecular and Cellular Biology ◽

10.1128/mcb.12.4.1507 ◽

1992 ◽

Vol 12 (4) ◽

pp. 1507-1514 ◽

Cited By ~ 30

Author(s):

C L Denis ◽

S C Fontaine ◽

D Chase ◽

B E Kemp ◽

L T Bemis

Keyword(s):

Protein Kinase ◽

Cyclic Amp ◽

Transcriptional Activation ◽

Growth Conditions ◽

Dependent Protein Kinase ◽

Inactive Form ◽

Dependent Protein ◽

Kinase Phosphorylation

Four ADR1c mutations that occur close to Ser-230 of the Saccharomyces cerevisiae transcriptional activator ADR1 and which greatly enhance the ability of ADR1 to activate ADH2 expression under glucose-repressed conditions have been shown to reduce or eliminate cyclic AMP-dependent protein kinase (cAPK) phosphorylation of Ser-230 in vitro. In addition, unregulated cAPK expression in vivo blocks ADH2 depression in an ADR1-dependent fashion in which ADR1c mutations display decreased sensitivity to unregulated cAPK activity. Taken together, these data have suggested that ADR1c mutations enhance ADR1 activity by blocking cAPK phosphorylation and inactivation of Ser-230. We have isolated and characterized an additional 17 ADR1c mutations, defining 10 different amino acid changes, that were located in the region defined by amino acids 227 through 239 of ADR1. Three observations, however, indicate that the ADR1c phenotype is not simply equivalent to a lack of cAPK phosphorylation. First, only some of these newly isolated ADR1c mutations affected the ability of yeast cAPK to phosphorylate corresponding synthetic peptides modeled on the 222 to 234 region of ADR1 in vitro. Second, we observed that strains lacking cAPK activity did not display enhanced ADH2 expression under glucose growth conditions. Third, when Ser-230 was mutated to a nonphosphorylatable residue, lack of cAPK activity led to a substantial increase in ADH2 expression under glucose-repressed conditions. Thus, while cAPK controls ADH2 expression and ADR1 is required for this control, cAPK acts by a mechanism that is independent of effects on ADR1 Ser-230. It was also observed that deletion of the ADR1c region resulted in an ADR1c phenotype. The ADR1c region is, therefore, involved in maintaining ADR1 in an inactive form. ADR1c mutations may block the binding of a repressor to ADR1 or alter the structure of ADR1 so that transcriptional activation regions become unmasked.

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