Afshari F S, Chu A K, Sato-Bigbee C
Department of Biochemistry and Molecular Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0614, USA.
J Neurosci Res. 2001 Oct 1;66(1):37-45. doi: 10.1002/jnr.1195.
Our previous results support the idea that CREB (cyclic AMP-response element binding protein) may be a mediator of neuroligand and growth factor signals that, coupled to different signal transduction pathways, play different roles at specific stages of oligodendrocyte development. In the early stages, when cells are immature precursors, CREB may play a role as a mediator of protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) pathways regulating cell proliferation. In contrast, at a later stage, when cells are already committed oligodendrocytes, CREB seems to play an important role as a mediator in the stimulation of myelin basic protein (MBP) expression by cyclic AMP (cAMP). In this study, we have investigated whether cAMP and CREB play a role in regulating the expression of all or on the other hand particular MBP isoforms. The results indicated that treatment of committed oligodendrocytes with the cAMP analogue db-cAMP results in a pattern of expression of MBP-related polypeptides that most closely resembles the pattern of MBPs observed in cerebra from adult animals. Experiments in which CREB expression was inhibited using a CREB antisense oligonucleotide, suggested that CREB is involved in the cAMP-dependent stimulation of all the MBP isoforms. In contrast, we have found that db-cAMP stimulates the expression of myelin proteolipid protein (PLP) in a process that occurs despite inhibition of CREB expression. These results support the idea that cAMP stimulates the maturation of oligodendrocytes and stress the fact multiple mechanisms may convey the action of this second messenger modulating oligodendrocyte differentiation and myelination.
我们之前的研究结果支持这样一种观点，即环磷腺苷反应元件结合蛋白（CREB）可能是神经配体和生长因子信号的介导物，这些信号与不同的信号转导途径相结合，在少突胶质细胞发育的特定阶段发挥不同作用。在早期阶段，当细胞是未成熟的前体细胞时，CREB可能作为蛋白激酶C（PKC）/丝裂原活化蛋白激酶（MAPK）途径的介导物发挥作用，调节细胞增殖。相比之下，在后期阶段，当细胞已经是成熟少突胶质细胞时，CREB似乎作为介导物在环磷腺苷（cAMP）刺激髓鞘碱性蛋白（MBP）表达中发挥重要作用。在本研究中，我们研究了cAMP和CREB在调节所有或特定MBP亚型表达中是否发挥作用。结果表明，用cAMP类似物二丁酰环磷腺苷（db-cAMP）处理成熟少突胶质细胞会导致MBP相关多肽的表达模式，该模式与成年动物大脑中观察到的MBP模式最为相似。使用CREB反义寡核苷酸抑制CREB表达的实验表明，CREB参与了cAMP依赖性对所有MBP亚型的刺激。相比之下，我们发现db-cAMP在抑制CREB表达的情况下仍能刺激髓鞘蛋白脂蛋白（PLP）的表达。这些结果支持了cAMP刺激少突胶质细胞成熟的观点，并强调了多种机制可能传递这种第二信使调节少突胶质细胞分化和髓鞘形成作用的事实。
