無論是在胚胎發(fā)育階段還是成體階段,，神經干細胞的自我增殖都受到內因基因表達水平及外因微環(huán)境的精細調控,，這種調控作用與神經系統(tǒng)的正常發(fā)育、腦功能的維持和修復都有密切關系,。
近日,，由中科院上海藥物研究所李佳研究員、南發(fā)俊研究員和馮林音研究員課題組等協(xié)作進行的對小分子化合物調控神經干細胞命運及其作用機制研究中,，首次發(fā)現(xiàn)了小分子化合物AICAR對永生化神經干細胞C17.2及來源于不同發(fā)展時期,，及不同部位來源的神經干細胞均有明顯誘導分化為神經膠質細胞的作用，該作用可能并不依賴于其傳統(tǒng)胞內靶點AMPK信號通路,。同時還發(fā)現(xiàn)AICAR能通過下調細胞內cyclin D及磷酸化Rb,，從而阻斷神經干細胞分裂周期，抑制其增殖速度,?；谙佘占っ敢种苿㊣TU、AMPK特異性抑制劑compound C及無活性突變形式DN-AMPK過表達能一定程度的阻斷AICAR的抑制增殖作用等的研究結果,，表明AICAR的這一抑制增殖作用可能仍然依賴于AMPK 信號通路的激活,。此外研究人員還觀察到低糖作為一種生理性的能量缺乏刺激，也能激活神經干細胞AMPK 信號通路,，同時通過下調cyclin D及Rb磷酸化水平引起其周期阻滯于G1/G0期,，從而抑制神經干細胞的增殖，該作用也同樣能一定程度被compound C及DN-AMPK過表達所逆轉,，這也再次提示了AMPK可能在面對外界能量匱乏環(huán)境下調控神經干細胞增殖中發(fā)揮重要作用。
以上結果已在《生物化學雜志》（J. Biol. Chem.）上發(fā)表,，為能量監(jiān)控器AMPK可能在神經干細胞乃至其他干細胞適應外界環(huán)境的生理過程中起基礎作用提供重要線索,。（生物谷Bioon.com）
生物谷推薦原始出處：
JBC January 14, 2009, doi: 10.1074/jbc.M806887200
AMP-activated Protein Kinase Is Involved in Neural Stem Cell Growth Suppression and Cell Cycle Arrest by 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and Glucose Deprivation by Down-regulating Phospho-retinoblastoma Protein and Cyclin D*
Yi Zang, Li-Fang Yu, Fa-Jun Nan, Lin-Yin Feng§ and Jia Li1
The fate of neural stem cells (NSCs), including their proliferation, differentiation, survival, and death, is regulated by multiple intrinsic signals and the extrinsic environment. We had previously reported that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) directly induces astroglial differentiation of NSCs by activation of the Janus kinase (JAK)/Signal transducer and activator of transcription 3 (STAT3) pathway independently of AMP-activated protein kinase (AMPK). Here, we reported the observation that AICAR inhibited NSC proliferation and its underlying mechanism. Analysis of caspase activity and cell cycle showed that AICAR induced G1/G0 cell cycle arrest in NSCs, associated with decreased levels of poly(ADP-ribose) polymerase, phospho-retinoblastoma protein (Rb), and cyclin D but did not cause apoptosis. Iodotubericidin and Compound C, inhibitors of adenosine kinase and AMPK, respectively, or overexpression of a dominant-negative mutant of AMPK, but not JAK inhibitor, were able to reverse the anti-proliferative effect of AICAR. Glucose deprivation also activated the AMPK pathway, induced G0/G1 arrest, and suppressed the proliferation of NSCs, an effect associated with decreased levels of phospho-Rb and cyclin D protein. Furthermore, Compound C and overexpression of dominant-negative AMPK in C17.2 NSCs could block the glucose deprivation-mediated down-regulation of cyclin D and partially reverse the suppression of proliferation. These results suggest that AICAR and glucose deprivation might induce G1/G0 cell cycle arrest and suppress proliferation of NSCs via phospho-Rb and cyclin D down-regulation. AMPK, but not JAK/STAT3, activation is key for this inhibitory effect and may play an important role in the responses of NSCs to metabolic stresses such as glucose deprivation.
