Poulsen Raewyn C, Carr Andrew J, Hulley Philippa A
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK.
Biochem Biophys Res Commun. 2015 Jun 19;462(1):78-84. doi: 10.1016/j.bbrc.2015.04.112. Epub 2015 Apr 30.
The FOXO family of forkhead transcription factors have a pivotal role in determining cell fate in response to oxidative stress. FOXO activity can either promote cell survival or induce cell death. Increased FOXO-mediated cell death has been implicated in the pathogenesis of degenerative diseases affecting musculoskeletal tissues. The aim of this study was to determine the conditions under which one member of the FOXO family, FOXO3a, promotes cell survival as opposed to cell death. Treatment of primary human tenocytes with 1 pM hydrogen peroxide for 18 h resulted in increased protein levels of FOXO3a. In peroxide-treated cells cultured in low serum media, FOXO3a inhibited cell proliferation and protected against apoptosis. However in peroxide treated cells cultured in high serum media, cell proliferation was unchanged but level of apoptosis significantly increased. Similarly, in tenocytes transduced to over-express FOXO3a, cell proliferation was inhibited and level of apoptosis unchanged in cells cultured in low serum. However there was a robust increase in cell death in FOXO3a-expressing cells cultured in high serum. Inhibition of cell proliferation in either peroxide-treated or FOXO3a-expressing cells cultured in high serum protected against apoptosis induction. Conversely, addition of a Chk2 inhibitor to peroxide-treated or FOXO3a-expressing cells overrode the inhibitory effect of FOXO3a on cell proliferation and led to increased apoptosis in cells cultured in low serum. This study demonstrates that proliferating cells may be particularly susceptible to the apoptosis-inducing actions of FOXO3a. Inhibition of cell proliferation by FOXO3a may be a critical event in allowing the pro-survival rather than the pro-apoptotic activity of FOXO3a to prevail.
叉头转录因子FOXO家族在决定细胞对氧化应激的命运反应中起关键作用。FOXO活性既可以促进细胞存活，也可以诱导细胞死亡。FOXO介导的细胞死亡增加与影响肌肉骨骼组织的退行性疾病的发病机制有关。本研究的目的是确定FOXO家族的一个成员FOXO3a促进细胞存活而非细胞死亡的条件。用1 pM过氧化氢处理原代人肌腱细胞18小时导致FOXO3a蛋白水平增加。在低血清培养基中培养的经过氧化氢处理的细胞中，FOXO3a抑制细胞增殖并防止细胞凋亡。然而，在高血清培养基中培养的经过氧化氢处理的细胞中，细胞增殖未改变，但细胞凋亡水平显著增加。同样，在转导以过表达FOXO3a的肌腱细胞中，在低血清中培养的细胞中细胞增殖受到抑制且细胞凋亡水平未改变。然而，在高血清中培养的表达FOXO3a的细胞中细胞死亡显著增加。在高血清中培养的经过氧化氢处理或表达FOXO3a的细胞中抑制细胞增殖可防止细胞凋亡诱导。相反，向经过氧化氢处理或表达FOXO3a的细胞中添加Chk2抑制剂可克服FOXO3a对细胞增殖的抑制作用，并导致在低血清中培养的细胞中细胞凋亡增加。本研究表明，增殖细胞可能特别容易受到FOXO3a诱导凋亡作用的影响。FOXO3a对细胞增殖的抑制可能是使FOXO3a的促存活而非促凋亡活性占优势的关键事件。
