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Dual activity of pyrrolidine dithiocarbamate on kappaB-dependent gene expression in U937 cells: II. Regulation by tumour necrosis factor-alpha.
Cell Signal. 1999 May; 11(5):371-83.CS

Abstract

In the human promonocytic U937 cell line, pyrrolidine dithiocarbamate (PDTC) was a potent inhibitor of the nuclear factor-kappaB (NF-kappaB) signalling pathway induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). However, PDTC did not inhibit tumour necrosis factor-alpha (TNF-alpha)-induced NF-kappaB DNA binding activity but potentiated the effect of TNF-alpha on kappaB-dependent gene expression. The stimulatory effect of PDTC with TNF-alpha was not observed with an HIV-1 LTR reporter construct containing two mutated kappaB binding sites or with a construct with a mutation of the activating protein (AP)-2 binding site located between the two kappaB elements. Two distinct signalling pathways, one mediated by TPA and the other by TNF-alpha, were shown to interact, functionally defining a threshold important in the inhibitory or stimulatory effect of PDTC on kappaB-dependent gene expression. Evidence that PDTC induced AP-1 DNA binding and AP-1 reporter gene activity, raised the hypothesis that the effect of PDTC was mediated by an interaction between the AP-1 pathway and p65(RelA). Co-transfection with expression vectors for p65(RelA) and the AP-1 subunits c-Fos and c-Jun resulted in a decrease in the stimulatory effect of PDTC on HIV-1 LTR activity. Co-transfection of p65(RelA) with Tam67, a dominant negative mutant of c-Jun defective in transactivation, stimulated the effect of PDTC on HIV-1 LTR activity. Evidence that the stimulatory effect of Tam67 with PDTC was reduced with c-Jun is consistent with the hypothesis.

Authors+Show Affiliations

Signal Transduction Laboratory, Pharmaceutical Discovery Division, SRI International, Menlo Park, CA 94025, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10376811

Citation

Watanabe, K, et al. "Dual Activity of Pyrrolidine Dithiocarbamate On kappaB-dependent Gene Expression in U937 Cells: II. Regulation By Tumour Necrosis Factor-alpha." Cellular Signalling, vol. 11, no. 5, 1999, pp. 371-83.
Watanabe K, Kazakova I, Furniss M, et al. Dual activity of pyrrolidine dithiocarbamate on kappaB-dependent gene expression in U937 cells: II. Regulation by tumour necrosis factor-alpha. Cell Signal. 1999;11(5):371-83.
Watanabe, K., Kazakova, I., Furniss, M., & Miller, S. C. (1999). Dual activity of pyrrolidine dithiocarbamate on kappaB-dependent gene expression in U937 cells: II. Regulation by tumour necrosis factor-alpha. Cellular Signalling, 11(5), 371-83.
Watanabe K, et al. Dual Activity of Pyrrolidine Dithiocarbamate On kappaB-dependent Gene Expression in U937 Cells: II. Regulation By Tumour Necrosis Factor-alpha. Cell Signal. 1999;11(5):371-83. PubMed PMID: 10376811.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual activity of pyrrolidine dithiocarbamate on kappaB-dependent gene expression in U937 cells: II. Regulation by tumour necrosis factor-alpha. AU - Watanabe,K, AU - Kazakova,I, AU - Furniss,M, AU - Miller,S C, PY - 1999/6/22/pubmed PY - 1999/6/22/medline PY - 1999/6/22/entrez SP - 371 EP - 83 JF - Cellular signalling JO - Cell Signal VL - 11 IS - 5 N2 - In the human promonocytic U937 cell line, pyrrolidine dithiocarbamate (PDTC) was a potent inhibitor of the nuclear factor-kappaB (NF-kappaB) signalling pathway induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). However, PDTC did not inhibit tumour necrosis factor-alpha (TNF-alpha)-induced NF-kappaB DNA binding activity but potentiated the effect of TNF-alpha on kappaB-dependent gene expression. The stimulatory effect of PDTC with TNF-alpha was not observed with an HIV-1 LTR reporter construct containing two mutated kappaB binding sites or with a construct with a mutation of the activating protein (AP)-2 binding site located between the two kappaB elements. Two distinct signalling pathways, one mediated by TPA and the other by TNF-alpha, were shown to interact, functionally defining a threshold important in the inhibitory or stimulatory effect of PDTC on kappaB-dependent gene expression. Evidence that PDTC induced AP-1 DNA binding and AP-1 reporter gene activity, raised the hypothesis that the effect of PDTC was mediated by an interaction between the AP-1 pathway and p65(RelA). Co-transfection with expression vectors for p65(RelA) and the AP-1 subunits c-Fos and c-Jun resulted in a decrease in the stimulatory effect of PDTC on HIV-1 LTR activity. Co-transfection of p65(RelA) with Tam67, a dominant negative mutant of c-Jun defective in transactivation, stimulated the effect of PDTC on HIV-1 LTR activity. Evidence that the stimulatory effect of Tam67 with PDTC was reduced with c-Jun is consistent with the hypothesis. SN - 0898-6568 UR - https://www.unboundmedicine.com/medline/citation/10376811/Dual_activity_of_pyrrolidine_dithiocarbamate_on_kappaB_dependent_gene_expression_in_U937_cells:_II__Regulation_by_tumour_necrosis_factor_alpha_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(99)00022-4 DB - PRIME DP - Unbound Medicine ER -