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The Study of Molecular Mechanism Involved in Apoptosis and H2AX Phosphorylation Induced by Imatinib in Chronic Myelogenous Leukemia Cells

Author: ZhangYanJun
Tutor: LuChengRong
School: Hebei North University
Course: Pathology and Pathophysiology
Keywords: chronic myelogenous leukemia phosphorylation caspase-3 caspase-3inhibitor Z-VAD mammalian STE20-like kinase1(Mst1) apoptosis imatinib histone H2AX
CLC: R733.72
Type: Master's thesis
Year: 2012
Downloads: 6
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Abstract


Aim:Histone H2AX is a novel tumor suppressor and its phosphorylation at the C terminus (Ser139and Tyr142) is involved in regulation of apoptosis of tumor cell. The aim of the present study was to characterize the signaling pathways in regulation of H2AX C-terminal phosphorylation and apoptosis induced by imatinib in chronic myelogenous leukemia cells (CML).Methods:The whole protein and histones were extracted from CML cells (K562) after treatment of imatinib and were subjected to western blotting analysis. The apoptosis of K562cells were tested by microscopy and flow cytometry. The molecular mechanism of apoptosis and H2AX phosphorylation in K562cells were characterized by the above methods.Results find that (1) Imatinib induced phosphorylation of histone H2AX at C-terminal (Ser139and Tyr142) in time-dependent and dose-dependent manners. However, H2AX acetylation (Lys5) was not affected by imatinib, although the acetylated H2AX (Lys5) maintained a high endogenous level in K562cells. The phosphorylation of histone H2AX(Ser139and Tyrl42) followed a parallel response with apoptosis of K562cells induced by imatinib, suggesting that H2AX (Ser139and Tyr142) phosphorylation is related with apoptosis in K562cells.(2) Imatinib stimulated caspase-3(34kDa), a hallmark of apoptosis, to form the active fragment (17kDa), which cleaved its down stream mammalian STE20-like kinase1(Mstl)(54kDa) to form the active fragment (34kDa). The activation of caspase-3and Mstl coincided with K562cells apoptosis, indicating that the caspase-3/Mstl pathway may be involved in regulation of H2AX phosphorylation (Serl39and Tyr142) and apoptosis in K562cells induced by imatinib.(3) The caspase-3inhibitor Z-VAD blocked the activation of caspase-3and Mstl, and phosphoryation of H2AX (Ser139and Tyr142) in K562cells trigged by imatinib. Meanwhile, the apoptosis in K562cells was also inhibited.(4) Imatinib induced expression of Williams-Beuren syndrome transcription factor (WSTF) but not wild-type p53-induced phosphatasel(Wipl).The Final conclsions are that the caspase-3/Mstl pathway is required for H2AX C-terminal phosphorylation (Ser139and Tyr142) and subsequent apoptosis induced by imatinib in K562cells.Meamwile, we initially yielded the other mechanisms of H2AX C-terminal phosphorylation (Tyr142).

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CLC: > Medicine, health > Oncology > Hematopoietic and lymphoid neoplasms > Leukemia > Chronic leukemia
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