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Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism.
Oncogene. 2003 Dec 04; 22(55):8881-90.O

Abstract

Transforming growth factor-beta (TGF-beta) plays complex roles in carcinogenesis, as it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. SMAD proteins transduce signals from the TGF-beta receptors to regulate the transcription of specific target genes. Crosstalks with other signaling pathways may contribute to the specificity of TGF-beta effects. In this report, we have investigated the effects of cyclic adenosine 3',5'-monophosphate (cAMP), a key second messenger in the cellular response to various hormones, on SMAD-dependent signaling in human HaCaT keratinocytes. Using either an artificial SMAD3/4-dependent reporter construct or the natural TGF-beta target, plasminogen activator inhibitor-1, we show that membrane-permeable dibutyryl cAMP, and other intracellular cAMP-elevating agents such as the phosphodiesterase inhibitor isobutyl-methylxanthine, the adenylate cyclase activator forskolin, or exogenous prostaglandin E2 (PGE2), interfere with TGF-beta-induced SMAD-specific gene transactivation. Inhibition of protein kinase A (PKA), the main downstream effector of cAMP, with H-89, suppressed cAMP-dependent repression of SMAD-driven gene expression. Inversely, coexpression of either an active PKA catalytic subunit or that of the cAMP response element (CRE)-binding protein (CREB) blocked SMAD-driven gene transactivation. cAMP-elevating agents did not inhibit nuclear translocation and DNA binding of SMAD3/4 complexes, but abolished the interactions of SMAD3 with the transcription coactivators CREB-binding protein (CBP) and p300 in a PKA-dependent manner. These results suggest that suppression of TGF-beta/SMAD signaling and resulting gene transactivation by cAMP-inducing agents occurs via PKA-dependent, CREB-mediated, disruption of SMAD-CBP/p300 complexes.

Authors+Show Affiliations

INSERM U532, Institut de Recherche sur la Peau, Université Paris VII, Hôpital Saint-Louis, F-75010 Paris, France.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14654784

Citation

Schiller, Meinhard, et al. "Cyclic Adenosine 3',5'-monophosphate-elevating Agents Inhibit Transforming Growth Factor-beta-induced SMAD3/4-dependent Transcription Via a Protein Kinase A-dependent Mechanism." Oncogene, vol. 22, no. 55, 2003, pp. 8881-90.
Schiller M, Verrecchia F, Mauviel A. Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. Oncogene. 2003;22(55):8881-90.
Schiller, M., Verrecchia, F., & Mauviel, A. (2003). Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. Oncogene, 22(55), 8881-90.
Schiller M, Verrecchia F, Mauviel A. Cyclic Adenosine 3',5'-monophosphate-elevating Agents Inhibit Transforming Growth Factor-beta-induced SMAD3/4-dependent Transcription Via a Protein Kinase A-dependent Mechanism. Oncogene. 2003 Dec 4;22(55):8881-90. PubMed PMID: 14654784.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. AU - Schiller,Meinhard, AU - Verrecchia,Frank, AU - Mauviel,Alain, PY - 2003/12/5/pubmed PY - 2004/1/10/medline PY - 2003/12/5/entrez SP - 8881 EP - 90 JF - Oncogene JO - Oncogene VL - 22 IS - 55 N2 - Transforming growth factor-beta (TGF-beta) plays complex roles in carcinogenesis, as it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. SMAD proteins transduce signals from the TGF-beta receptors to regulate the transcription of specific target genes. Crosstalks with other signaling pathways may contribute to the specificity of TGF-beta effects. In this report, we have investigated the effects of cyclic adenosine 3',5'-monophosphate (cAMP), a key second messenger in the cellular response to various hormones, on SMAD-dependent signaling in human HaCaT keratinocytes. Using either an artificial SMAD3/4-dependent reporter construct or the natural TGF-beta target, plasminogen activator inhibitor-1, we show that membrane-permeable dibutyryl cAMP, and other intracellular cAMP-elevating agents such as the phosphodiesterase inhibitor isobutyl-methylxanthine, the adenylate cyclase activator forskolin, or exogenous prostaglandin E2 (PGE2), interfere with TGF-beta-induced SMAD-specific gene transactivation. Inhibition of protein kinase A (PKA), the main downstream effector of cAMP, with H-89, suppressed cAMP-dependent repression of SMAD-driven gene expression. Inversely, coexpression of either an active PKA catalytic subunit or that of the cAMP response element (CRE)-binding protein (CREB) blocked SMAD-driven gene transactivation. cAMP-elevating agents did not inhibit nuclear translocation and DNA binding of SMAD3/4 complexes, but abolished the interactions of SMAD3 with the transcription coactivators CREB-binding protein (CBP) and p300 in a PKA-dependent manner. These results suggest that suppression of TGF-beta/SMAD signaling and resulting gene transactivation by cAMP-inducing agents occurs via PKA-dependent, CREB-mediated, disruption of SMAD-CBP/p300 complexes. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/14654784/Cyclic_adenosine_3'5'_monophosphate_elevating_agents_inhibit_transforming_growth_factor_beta_induced_SMAD3/4_dependent_transcription_via_a_protein_kinase_A_dependent_mechanism_ L2 - https://doi.org/10.1038/sj.onc.1206871 DB - PRIME DP - Unbound Medicine ER -