EGF AND WNT SIGNAL INTEGRATION BY C ELEGANS HOX GENES

线虫 HOX 基因对 EGF 和 WNT 信号的整合

• 批准号: 6518849
• 负责人: LISA R GIRARD
• 金额: $ 4.42万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6518849
• 关键词: Caenorhabditis elegans; biological signal transduction; developmental genetics; epidermal growth factor; gene expression; genetic regulation; genetic regulatory element; protein tyrosine kinase

The specification of cell-fate by the integration of multiple signaling pathways is an emerging paradigm in developmental gene regulation. At least two cases of signal integration are necessary in C. elegans for correct cell fate specification. In the hermaphrodite vulva, integration EGF and Wnt pathway signals are required for specification of the vulval precursor cells. In the P12 neuroectoblast cell in the tail, integration of EGF and Wnt pathway signals are again required to effect P12 fate. In both these cases, integration of the two pathways results in the activation of a hox gene, lin-39 in the vulva and egl-5 in P12. The goal of this proposal is to define and compare the modes of signal integration in these two cases that lead to hox gene activation. I aim to achieve these goals by isolating upstream factors required for correct lin-39 and egl-5 expression and by defining cis-acting elements in lin-39 and egl-5 required for their endogenous expression pattern. The important role the highly conserved EGF/RAS/RAF and Wnt pathways play in animal cell proliferation and differentiation necessitates their understanding. It has been found that up to ninety percent of certain types of carcinomas have mutated RAS genes, thus it is essential we understand how these pathways work in concert in normal differentiation in order that we can understand the oncogenic consequences due to alterations in these pathways.

通过多种信号通路的整合来规范细胞命运是发育基因调控的一个新兴范例。在秀丽隐杆线虫中，至少有两种情况的信号整合是正确的细胞命运规范所必需的。在雌雄同体的外阴中，外阴前体细胞的分化需要整合EGF和Wnt信号。在尾部的P12神经外胚细胞中，EGF和Wnt通路信号的整合再次需要影响P12的命运。在这两种情况下，两种途径的整合导致了一个hox基因的激活，即外阴中的lin-39和P12中的egl-5。本提案的目的是定义和比较这两种情况下导致hox基因激活的信号整合模式。我的目标是通过分离正确表达lin-39和egl-5所需的上游因子，并通过定义lin-39和egl-5内源性表达模式所需的顺式作用元件来实现这些目标。高度保守的EGF/RAS/RAF和Wnt通路在动物细胞增殖和分化中所起的重要作用值得我们进一步了解。已经发现，高达90%的某些类型的癌症都有RAS基因突变，因此，我们必须了解这些途径如何在正常分化中协同工作，以便我们能够了解由于这些途径的改变而导致的致癌后果。