INVESTIGADORES
MARINO Veronica Julieta
artículos
Título:
A chimeric cyclic interferon-alpha2b peptide induces apoptosis by sequential activation of phosphatidylinositol 3-kinase, protein kinase-C delta and p38 MAPK
Autor/es:
VIVIANA C. BLANK; BERTUCCI L.; VERÓNICA A. FURMENTO; CLARA PEÑA; JULIETA MARINO; LEONOR P. ROGUIN
Revista:
EXPERIMENTAL CELL RESEARCH
Editorial:
ELSEVIER INC
Referencias:
Lugar: Amsterdam ; Año: 2013 vol. 319 p. 1471 - 1481
ISSN:
0014-4827
Resumen:
We have previously demonstrated that tyrosine phosphorylation of STAT1/3 and p38mitogen-activated protein kinase (p38MAPK) activation are involved in the apoptotic response triggered by a chimeric cyclic peptide of the interferon-alpha2b (IFN-alpha2b) in WISH cells. Since the peptide also induced serine phosphorylation of STAT proteins, in the present study we examined the kinase involved in serine STAT1 phosphorylation and the signalling effectors acting upstream such activation. We first  found that p38MAPK is involved in serine STAT1 phosphorylation, since a reduction of phophoserine-STAT1 levels was evident after incubating WISH cells with cyclic  peptide in the presence of a p38 pharmacological inhibitor or a dominant-negative p38 mutant. Next, we demonstrated that the peptide induced activation of protein kinase C delta (PKCdelta). Based on this finding, the role of this kinase was then evaluated. After incubating WISH cells with a PKCdelta inhibitor or after decreasing PKCdelta expression levels by RNA interference, both peptide-induced serine STAT1 and p38 phosphorylation levels were significantly decreased, indicating that PKCdelta functions as an upstream regulator of p38. We also showed that PKCdelta and p38 activation stimulated by the peptide was inhibited by a specific pharmacological inhibitor of phosphatidy- linositol 3-kinase (PI3K) orbyadominant-negative p85PI3K-regulatory subunit, suggesting that PI3K is upstream in the signalling cascade. In addition, the role of PI3K and PKCdelta in cyclic peptide- induced apoptosis was examined. Both signalling effectors were found to regulate the anti- proliferativa activity and the apoptotic response triggered by the cyclic peptide in WISH cells. In conclusion, we herein demonstrated that STAT1 serine phosphorylation is mediated by the sequential activation of PI3K, PKCdelta and p38 MAPK. This signalling cascade contributes to the antitumor effect induced by the chimeric IFN-alpha2b cyclic peptide in WISH cells.