REGULATION OF CELL PROLIFERATION BY GENES OF THE MYB FAMILY

本建议的目的是评估以下方面的相对贡献： myb家族的基因（A-myb、B-myb和c-myb）与 造血和非造血细胞增殖的调节 细胞 初步证据表明B-myb是c-myb的等价物 在非造血细胞中，虽然B-myb和c-myb可以反式激活 不同的基因，或者它们的反式激活能力不同， 结构域或与同一靶标中的myb结合位点的亲和力 基因. A-myb的作用还不太清楚，在某些肿瘤细胞系中， 似乎负调节菌落形成，也许是通过 通过与以下物质的相互作用拮抗c-myb和/或B-myb的活性： Myb（c-myb和/或B-myb）调节基因的Myb结合位点或通过 激活参与细胞生长负调控的基因。 然而，A-myb在成纤维细胞中的异位表达加速了细胞周期， 进展，提高了以下可能性：I）A-myb发挥不同的作用， 在不同细胞类型中的功能;或ii）A-myb的后果 在不同的细胞类型中活性不同。 通过剖析差异 在A-myb、B-myb和c-myb的活性方面，拟议的研究1）将 揭示了细胞增殖控制的机制， 同一家庭发挥互补或竞争作用; 2）可能提供 基于抑制的新型治疗干预的基本原理 Myb家族基因的活性。

The objective of this proposal is to assess the relative contribution of the genes of the myb family (A-myb, B-myb and c-myb) to the regulation of cell proliferation in hematopoietic and non-hematopoietic cells. Preliminary evidence suggests that B-myb is a c-myb equivalent in non-hematopoietic cells, although B-myb and c-myb may transactivate different genes, or differ in the potency of their transactivating domains or in the affinity to myb binding sites in the same target genes. The role of A-myb is less understood; in certain tumor lines it appears to negatively regulate colony formation, perhaps by antagonizing the activity of c-myb and/or B-myb via interaction with Myb binding sites of Myb (c-myb and/or B-myb)-regulated genes or by activating genes involved in negative regulation of cell growth. However, ectopic A-myb expression in fibroblasts accelerates cell cycle progression, raising the possibility that: I) A-myb exerts distinct functions in different cell types; or ii) the consequences of A-myb activity are different in different cell types. By dissecting differences in the activity of A-myb, B-myb and c-myb, the proposed studies 1) will reveal mechanisms of cell proliferation control in which genes of the same family play complementary or competing roles; and 2) might provide the rationale for novel therapeutic interventions based on suppressing the activity of genes of the Myb family.