Mechanisms of DLK regulation and action in cell proliferation/Mécanismes de régulation et d'action de la kinase DLK au cours de la proliferation cellulaire

多细胞生物体中的细胞通过许多信号分子相互通信，以控制它们的生长，分化和代谢。由这些分子编码的信息在细胞表面接收，并通过信号通路网络在细胞内传递，从而调节基因表达。参与细胞增殖控制的关键途径是激活所谓的促分裂原活化蛋白激酶（MAPK）激酶家族的那些途径。在人类中，MAPK的调节和功能的改变与各种疾病相关，包括糖尿病和癌症。作为表征MAPK信号在正常细胞中调节的分子机制的手段，我们的研究小组研究了DLK的作用和特定性质，DLK是生物体发育，细胞分化和细胞死亡所需的MAPK上游激活剂。有趣的是，最近在我们实验室进行的实验也揭示了DLK参与细胞对生长因子的反应。然而，DLK究竟如何介导增殖信号是一个重要的问题仍然没有完全回答。因此，本提案的总体目标是进一步阐明DLK在细胞增殖中的潜在调节和作用的机制。这些信息可能对癌症治疗新策略的设计具有重要意义。

Cells in multicellular organisms communicate with each other through a number of signaling molecules in order to control their growth, differentiation and metabolism. Information encoded by these molecules is received at the cell surface and transmitted within the cell by networks of signaling pathways that consequently modulate gene expression. Among the key pathways involved in cell proliferation control are those which activate the so-called mitogen-activated protein kinase (MAPK) family of kinases. In human, alterations in regulation and function of MAPKs are associated with various diseases, including diabetes and cancer. As a mean to characterize the molecular mechanisms by which MAPK signaling is regulated in normal cells, our research group investigates the roles and the specific properties of DLK, a MAPK upstream activator that is required for organism development, cell differentiation and cell death. Interestingly, recent experiments carried out in our laboratory have also revealed the involvement of DLK in the response of cells to growth factors. However, exactly how DLK mediates proliferation signals is an important question still not fully answered. Consequently, the overall goal of the present proposal is to clarify further the mechanisms underlying regulation and role of DLK in cell proliferation. This information may have fundamental implications in the design of novel strategies for cancer treatment.