期刊
BLOOD
卷 115, 期 7, 页码 1416-1424出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-07-234963
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资金
- National Institutes of Health [R01DK059380]
- Hematology Training Grant [T32HL007147]
- Flow Cytometry and Radiation Resources Core Facilities of the Case Comprehensive Cancer Center [P30CA43703]
- [SFB-F28]
- Austrian Science Fund (FWF) [F 2807] Funding Source: researchfish
Phosphorylated signal transducer and activator of transcription 5 (STAT5) is a biomarker and potential molecular target for hematologic malignancies. We have shown previously that lethal myeloproliferative disease (MPD) in mice mediated by persistently activated STAT5 (STAT5a(S711F)) requires the N-domain, but the mechanism was not defined. We now demonstrate by retrovirally complementing STAT5ab(null/null) primary mast cells that relative to wild-type STAT5a, STAT5a lacking the N-domain (STAT5a Delta N) ineffectively protected against cytokine withdrawal-induced cell death. Both STAT5a and STAT5a Delta N bound to a site in the bcl-2 gene and both bound near the microRNA 15b/16 cluster. However, only STAT5a could effectively induce bcl-2 mRNA and reciprocally suppress miR15b/16 leading to maintained bcl-2 protein levels. After retroviral complementation of STAT5ab(null/null) fetal liver cells and transplantation, persistently active STAT5a(S711F) lacking the N-domain (STAT5a Delta N-S711F) was insufficient to protect c-Kit(+)Lin(-)Sca-1(+) (KLS) cells from apoptosis and unable to induce bcl-2 expression, whereas STAT5a(S711F) caused robust KLS cell expansion, induction of bcl-2, and lethal MPD. Severe attenuation of MPD by STAT5a Delta N-S711F was reversed by H2k/bcl-2 transgenic expression. Overall, these studies define N-domain dependent survival signaling as an Achilles heel of persistent STAT5 activation and highlight the potential therapeutic importance of targeting STAT5 N-domain-mediated regulation of bcl-2 family members. (Blood. 2010; 115: 1416-1424)
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