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Titolo:
Biologic sequelae of interleukin-6 induced P13-K/Akt signaling in multiplemyeloma
Autore:
Hideshima, T; Nakamura, N; Chauhan, D; Anderson, KC;
Indirizzi:
Dana Farber Canc Inst, Dept Adult Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA Dana Farber Canc Inst Boston MA USA 02115 eloma Ctr, Boston, MA 02115 USA Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA Harvard Univ BostonMA USA 02115 Sch Med, Dept Med, Boston, MA 02115 USA
Titolo Testata:
ONCOGENE
fascicolo: 42, volume: 20, anno: 2001,
pagine: 5991 - 6000
SICI:
0950-9232(20010920)20:42<5991:BSOIIP>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-B; DEXAMETHASONE-INDUCED APOPTOSIS; PLECKSTRIN-HOMOLOGY DOMAIN; PHOSPHATIDYLINOSITOL 3-KINASE/AKT; CELL-GROWTH; TRANSDUCTION PATHWAY; INHIBITS APOPTOSIS; PLASMA-CELLS; PHOSPHORYLATION; ACTIVATION;
Keywords:
multiple myeloma; IL-6; SHP2; P13-K; Akt; apoptosis; caspase-9;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Anderson, KC Dana Farber Canc Inst, Dept Adult Oncol, Jerome Lipper Multiple Myeloma Ctr, M557,44 Binney St, Boston, MA 02115 USA Dana Farber Canc Inst M557,44 Binney St Boston MA USA 02115 A
Citazione:
T. Hideshima et al., "Biologic sequelae of interleukin-6 induced P13-K/Akt signaling in multiplemyeloma", ONCOGENE, 20(42), 2001, pp. 5991-6000

Abstract

Previous studies demonstrate that interleukin-6 (IL-6) mediates growth andsurvival in human multiple myeloma (MM) cells via the MEK/MAPK and JAK/STAT signaling pathways, respectively. IL-6 also confers protection against Dexamethasone (Dex)-induced apoptosis via activation of protein tyrosine phosphatase (SHP2). In the current study, we characterized IL-6 triggered phophatidylinositol-3 kinase/Akt kinase (PI3K/Akt) signaling in MM cells. IL-6 induces Akt/PKB phosphorylation in a time and dose dependent manner in MMAS MM cells. IL-6 also induced phosphorylation of downstream targets of Akt, including Bad, GSK-3 beta, and FKHR, confirming Akt activation. Inhibition of Akt activation by the PI3-K inhibitor LY294002 partially blocked IL-6 triggered MEK/MAPK activation and proliferation in MMAS cells, suggesting cross-talk between PI3-K and MEK signaling. We demonstrate that Dex-induced apoptosis in MM.1S cells is mediated by downstream activation of caspase-9, with resultant caspase-3 cleavage; and conversely, that IL-6 triggers activation of PI3-K and its association with SHP2, inactivates caspase-9, and protects against Dex-induced apoptosis. LY294002 completely abrogates this signaling cascade, further confirming the importance of PI3-K/Akt signaling in conferring the protective effect of IL-6 against Dex-induced apoptosis. Finally, we show that IL-6 triggered PI3-K/Akt signaling in MMAS cells inactivates forkhead transcriptional factor (FKHR), with related G1/S phase transition, whereas LY294002 blocks this signaling, resulting in upregulation of p27(KIPI) and G1 growth arrest. Our data therefore suggest that PI3-K/ Akt signaling mediates growth, survival, and cell cycle regulatory effects of IL-6 in MM.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/09/20 alle ore 14:05:49