Journal Article

Cigarette smoke condensate activates nuclear transcription factor-κB through phosphorylation and degradation of IκBα: correlation with induction of cyclooxygenase-2

Ruby John Anto, Asok Mukhopadhyay, Shishir Shishodia, C. Gary Gairola and Bharat B. Aggarwal

in Carcinogenesis

Volume 23, issue 9, pages 1511-1518
Published in print September 2002 | ISSN: 0143-3334
Published online September 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.9.1511
Cigarette smoke condensate activates nuclear transcription factor-κB through phosphorylation and degradation of IκBα: correlation with induction of cyclooxygenase-2

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Cigarette smoke (CS) contains several carcinogens known to initiate and promote tumorigenesis and metastasis. Because various genes that mediate carcinogenesis and tumorigenesis are regulated by nuclear factor-κB (NF-κB), we postulated that the effects of CS must be mediated through activation of this transcription factor. Therefore, in the present report we investigated whether cigarette smoke condensate (CSC) activates NF-κB, and whether the pathway employed for activation is similar to that of TNF, one of the potent activators of NF-κB. Our results show that the treatment of human histiocytic lymphoma U-937 cells with CSC activated NF-κB in a dose- and time-dependent manner. The kinetics of NF-κB activation by CSC was comparable with that of TNF. CSC-induced NF-κB activation was not cell type-specific, as it also activated NF-κB in T cells (Jurkat), lung cells (H1299), and head and neck squamous cell lines (1483 and 14B). Activation of NF-κB by CSC correlated with time-dependent degradation of IκBα, an inhibitor of NF-κB. Further studies revealed that CSC induced phosphorylation of the serine residue at position 32 in IκBα. In vitro immunocomplex kinase assays showed that CSC activated IκBα kinase (IKK). The suppression of CSC-activated NF-κB-dependent reporter gene expression by dominant negative form of IκBα, TRAF2, NIK and IKK suggests a similarity to the TNF-induced pathway for NF-κB. CSC also induced the expression of cyclooxygenase-2, an NF-κB regulated gene product. Overall, our results indicate that through phosphorylation and degradation of IκBα, CSC can activate NF-κB in a wide a variety of cells, and this may play a role in CS-induced carcinogenesis.

Keywords: B[a]P, benzo[a]pyrene; COPD, chronic obstructive pulmonary disease; COX-2, cyclooxygenase; CS, cigarette smoke; CSC, cigarette smoke condensate; EMSA, electrophoretic mobility shift assay; IL, interleukin; NF-κB, nuclear transcription factor-κB

Journal Article.  6735 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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