无论是在胚胎发育阶段还是成体阶段，神经干细胞的自我增殖都受到内因基因表达水平及外因微环境的精细调控，这种调控作用与神经系统的正常发育、脑功能的维持和修复都有密切关系。
近日，由中科院上海药物研究所李佳研究员、南发俊研究员和冯林音研究员课题组等协作进行的对小分子化合物调控神经干细胞命运及其作用机制研究中，首次发现了小分子化合物AICAR对永生化神经干细胞C17.2及来源于不同发展时期，及不同部位来源的神经干细胞均有明显诱导分化为神经胶质细胞的作用，该作用可能并不依赖于其传统胞内靶点AMPK信号通路。同时还发现AICAR能通过下调细胞内cyclin D及磷酸化Rb，从而阻断神经干细胞分裂周期，抑制其增殖速度。基于腺苷激酶抑制剂ITU、AMPK特异性抑制剂compound C及无活性突变形式DN-AMPK过表达能一定程度的阻断AICAR的抑制增殖作用等的研究结果，表明AICAR的这一抑制增殖作用可能仍然依赖于AMPK 信号通路的激活。此外研究人员还观察到低糖作为一种生理性的能量缺乏刺激，也能激活神经干细胞AMPK 信号通路，同时通过下调cyclin D及Rb磷酸化水平引起其周期阻滞于G1/G0期，从而抑制神经干细胞的增殖，该作用也同样能一定程度被compound C及DN-AMPK过表达所逆转，这也再次提示了AMPK可能在面对外界能量匮乏环境下调控神经干细胞增殖中发挥重要作用。
以上结果已在《生物化学杂志》（J. Biol. Chem.）上发表，为能量监控器AMPK可能在神经干细胞乃至其他干细胞适应外界环境的生理过程中起基础作用提供重要线索。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
