Journal Article

Recovery of gap junctional intercellular communication after phorbol ester treatment requires proteasomal degradation of protein kinase C

Edward Leithe, Véronique Cruciani, Tore Sanner, Svein-Ole Mikalsen and Edgar Rivedal

in Carcinogenesis

Volume 24, issue 7, pages 1239-1245
Published in print July 2003 | ISSN: 0143-3334
Published online July 2003 | e-ISSN: 1460-2180 | DOI:

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Reversible down-regulation of gap junctional intercellular communication (GJIC) is proposed to be an important cellular mechanism in tumor promotion. Gap junction function is modified by a variety of tumor promoters, including the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of cells with TPA results in the activation and subsequent depletion of the TPA-responsive protein kinase C (PKC) isoforms. TPA-induced degradation of the PKC isoforms α, δ and ϵ was recently shown to occur via the ubiquitin–proteasome pathway. In the present study we investigated the role of the proteasome in the TPA-induced modification of GJIC in IAR20 rat liver epithelial cells. TPA exposure of IAR20 cells induced hyperphosphorylation of gap junction protein connexin43 and inhibition of GJIC. Prolonged TPA treatment induced down-regulation of PKCα, δ and ϵ and a reduction in the total PKC activity, which was associated with recovery of GJIC. Co-treatment of IAR20 cells with TPA and the proteasomal inhibitor MG132 suppressed down-regulation of PKCα, δ and ϵ and caused prolonged PKC activity. Under these conditions, the recovery of GJIC was blocked. The general PKC inhibitor GF109203X reversed the effect of MG132, indicating that the prolonged TPA-induced inhibition of GJIC caused by MG132 was due to the prolonged PKC activity. These results indicate that proteasomal degradation of PKC is one mechanism by which the recovery of GJIC after TPA treatment is regulated.

Keywords: Cx43, connexin43; DMSO, dimethyl sulfoxide; DMEM, Dulbecco's modified Eagle's medium; ERK, extracellular signal-regulated kinase; GJIC, gap junctional intercellular communication; PBS, phosphate-buffered saline; PKC, protein kinase C; TPA, 12-O-tetradecanoylphorbol-13-acetate

Journal Article.  5327 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics