Putative conventional protein kinase C inhibitor Gödecke 6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H- indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Stimulates transglutaminase activity in primary mouse epidermal keratinocytes

Brian A. Shapiro, Sagarika Ray, Eunmi Jung, William T. Allred, Wendy B Bollag

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Abstract

Much data in the literature suggest a role for protein kinase C (PKC) in regulating keratinocyte proliferation and differentiation. Nevertheless, the exact role of this family of isoenzymes is unclear, since PKC agonists (e.g., phorbol esters) are known to stimulate expression of both proliferative and differentiative markers in keratinocytes. Similarly, PKC inhibitors have been demonstrated both to inhibit [2-[1-3(aminopropyl)indol-3-yl]- 3(1-methyl-1H-indol-3-yl)maleimide, acetate (Ro 31-7549) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-(1-methyl-1H-indol-3yl) maleimide (Ro 31-8220)] and to induce (staurosporine) keratinocyte differentiation. In this study, we examined the role of the PKC inhibitor, Gödecke 6976 (Gö6976) [12-(2-cyanoethyl)-6,7,12,13 -tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo (3,4-c)-carbazole], on keratinocyte proliferation, as measured by DNA synthesis, and differentiation, as monitored by transglutaminase activity. This compound is reported to be selective for the conventional PKC isoforms, of which keratinocytes express only PKCα, and for protein kinase D (PKD; also known as PKCμ. We report that Gö6976 stimulated transglutaminase activity. Consistent with this effect, Gö6976 also potently inhibited [3H]thymidine incorporation (a half-maximal inhibitory concentration of ∼0.1 μM). In addition, Gö6976 (1 μM) was able to enhance the stimulation of transglutaminase activity by 1,25- dihydroxyvitamin D3 but had no effect on D3-induced expression of keratin-1. Conversely, Gö6983 [2-[1-(3-dimethylaminopropy)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], a similar compound that also selectively inhibits conventional PKCα, but not PKD, had little or no effect on DNA synthesis or transglutaminase activity (up to 1 μM). The effect of Gö6976 was not due to cytotoxicity as its effect on thymidine incorporation was largely reversible, and its stimulation of transglutaminase activity could be inhibited by another general PKC inhibitor, bisindolylmaleimide I. Therefore, our results suggest a proproliferative, antidifferentiative role for PKD in epidermal maturation.

Original languageEnglish (US)
Pages (from-to)352-358
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume302
Issue number1
DOIs
StatePublished - Jul 4 2002

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Transglutaminases
Protein C Inhibitor
Protein Kinase Inhibitors
Keratinocytes
Protein Kinase C
Thymidine
Keratin-1
Staurosporine
goedecke 6976
DNA
Phorbol Esters
Isoenzymes
Protein Isoforms
Acetates

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

@article{2c8af86a51e045129eecd9b7530e96b1,
title = "Putative conventional protein kinase C inhibitor G{\"o}decke 6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H- indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Stimulates transglutaminase activity in primary mouse epidermal keratinocytes",
abstract = "Much data in the literature suggest a role for protein kinase C (PKC) in regulating keratinocyte proliferation and differentiation. Nevertheless, the exact role of this family of isoenzymes is unclear, since PKC agonists (e.g., phorbol esters) are known to stimulate expression of both proliferative and differentiative markers in keratinocytes. Similarly, PKC inhibitors have been demonstrated both to inhibit [2-[1-3(aminopropyl)indol-3-yl]- 3(1-methyl-1H-indol-3-yl)maleimide, acetate (Ro 31-7549) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-(1-methyl-1H-indol-3yl) maleimide (Ro 31-8220)] and to induce (staurosporine) keratinocyte differentiation. In this study, we examined the role of the PKC inhibitor, G{\"o}decke 6976 (G{\"o}6976) [12-(2-cyanoethyl)-6,7,12,13 -tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo (3,4-c)-carbazole], on keratinocyte proliferation, as measured by DNA synthesis, and differentiation, as monitored by transglutaminase activity. This compound is reported to be selective for the conventional PKC isoforms, of which keratinocytes express only PKCα, and for protein kinase D (PKD; also known as PKCμ. We report that G{\"o}6976 stimulated transglutaminase activity. Consistent with this effect, G{\"o}6976 also potently inhibited [3H]thymidine incorporation (a half-maximal inhibitory concentration of ∼0.1 μM). In addition, G{\"o}6976 (1 μM) was able to enhance the stimulation of transglutaminase activity by 1,25- dihydroxyvitamin D3 but had no effect on D3-induced expression of keratin-1. Conversely, G{\"o}6983 [2-[1-(3-dimethylaminopropy)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], a similar compound that also selectively inhibits conventional PKCα, but not PKD, had little or no effect on DNA synthesis or transglutaminase activity (up to 1 μM). The effect of G{\"o}6976 was not due to cytotoxicity as its effect on thymidine incorporation was largely reversible, and its stimulation of transglutaminase activity could be inhibited by another general PKC inhibitor, bisindolylmaleimide I. Therefore, our results suggest a proproliferative, antidifferentiative role for PKD in epidermal maturation.",
author = "Shapiro, {Brian A.} and Sagarika Ray and Eunmi Jung and Allred, {William T.} and Bollag, {Wendy B}",
year = "2002",
month = "7",
day = "4",
doi = "10.1124/jpet.302.1.352",
language = "English (US)",
volume = "302",
pages = "352--358",
journal = "The Journal of pharmacology and experimental therapeutics",
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publisher = "American Society for Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - Putative conventional protein kinase C inhibitor Gödecke 6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H- indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Stimulates transglutaminase activity in primary mouse epidermal keratinocytes

AU - Shapiro, Brian A.

AU - Ray, Sagarika

AU - Jung, Eunmi

AU - Allred, William T.

AU - Bollag, Wendy B

PY - 2002/7/4

Y1 - 2002/7/4

N2 - Much data in the literature suggest a role for protein kinase C (PKC) in regulating keratinocyte proliferation and differentiation. Nevertheless, the exact role of this family of isoenzymes is unclear, since PKC agonists (e.g., phorbol esters) are known to stimulate expression of both proliferative and differentiative markers in keratinocytes. Similarly, PKC inhibitors have been demonstrated both to inhibit [2-[1-3(aminopropyl)indol-3-yl]- 3(1-methyl-1H-indol-3-yl)maleimide, acetate (Ro 31-7549) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-(1-methyl-1H-indol-3yl) maleimide (Ro 31-8220)] and to induce (staurosporine) keratinocyte differentiation. In this study, we examined the role of the PKC inhibitor, Gödecke 6976 (Gö6976) [12-(2-cyanoethyl)-6,7,12,13 -tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo (3,4-c)-carbazole], on keratinocyte proliferation, as measured by DNA synthesis, and differentiation, as monitored by transglutaminase activity. This compound is reported to be selective for the conventional PKC isoforms, of which keratinocytes express only PKCα, and for protein kinase D (PKD; also known as PKCμ. We report that Gö6976 stimulated transglutaminase activity. Consistent with this effect, Gö6976 also potently inhibited [3H]thymidine incorporation (a half-maximal inhibitory concentration of ∼0.1 μM). In addition, Gö6976 (1 μM) was able to enhance the stimulation of transglutaminase activity by 1,25- dihydroxyvitamin D3 but had no effect on D3-induced expression of keratin-1. Conversely, Gö6983 [2-[1-(3-dimethylaminopropy)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], a similar compound that also selectively inhibits conventional PKCα, but not PKD, had little or no effect on DNA synthesis or transglutaminase activity (up to 1 μM). The effect of Gö6976 was not due to cytotoxicity as its effect on thymidine incorporation was largely reversible, and its stimulation of transglutaminase activity could be inhibited by another general PKC inhibitor, bisindolylmaleimide I. Therefore, our results suggest a proproliferative, antidifferentiative role for PKD in epidermal maturation.

AB - Much data in the literature suggest a role for protein kinase C (PKC) in regulating keratinocyte proliferation and differentiation. Nevertheless, the exact role of this family of isoenzymes is unclear, since PKC agonists (e.g., phorbol esters) are known to stimulate expression of both proliferative and differentiative markers in keratinocytes. Similarly, PKC inhibitors have been demonstrated both to inhibit [2-[1-3(aminopropyl)indol-3-yl]- 3(1-methyl-1H-indol-3-yl)maleimide, acetate (Ro 31-7549) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-(1-methyl-1H-indol-3yl) maleimide (Ro 31-8220)] and to induce (staurosporine) keratinocyte differentiation. In this study, we examined the role of the PKC inhibitor, Gödecke 6976 (Gö6976) [12-(2-cyanoethyl)-6,7,12,13 -tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo (3,4-c)-carbazole], on keratinocyte proliferation, as measured by DNA synthesis, and differentiation, as monitored by transglutaminase activity. This compound is reported to be selective for the conventional PKC isoforms, of which keratinocytes express only PKCα, and for protein kinase D (PKD; also known as PKCμ. We report that Gö6976 stimulated transglutaminase activity. Consistent with this effect, Gö6976 also potently inhibited [3H]thymidine incorporation (a half-maximal inhibitory concentration of ∼0.1 μM). In addition, Gö6976 (1 μM) was able to enhance the stimulation of transglutaminase activity by 1,25- dihydroxyvitamin D3 but had no effect on D3-induced expression of keratin-1. Conversely, Gö6983 [2-[1-(3-dimethylaminopropy)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide], a similar compound that also selectively inhibits conventional PKCα, but not PKD, had little or no effect on DNA synthesis or transglutaminase activity (up to 1 μM). The effect of Gö6976 was not due to cytotoxicity as its effect on thymidine incorporation was largely reversible, and its stimulation of transglutaminase activity could be inhibited by another general PKC inhibitor, bisindolylmaleimide I. Therefore, our results suggest a proproliferative, antidifferentiative role for PKD in epidermal maturation.

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