BCL-2 Proteins and the IGF-1 Receptor

本项目的目的是确定凋亡的两个主要参与者，1型胰岛素样生长因子受体（IGF- IR）和Bcl-2家族蛋白，特别是Bcl-Xl和Bad之间的关系。我们实验室和文献的初步结果表明，这两个系统之间存在联系，我们打算探索IGF-IR和这些蛋白质在凋亡过程中相互调节的机制。我们将关注两种不同的系统，它们都有各自的优点和缺点。在第一个模型中，我们将使用锚定不依赖条件下的小鼠胚胎成纤维细胞（MEF），因为拒绝附着于基质的细胞通常比单层培养的细胞更容易发生凋亡（anoikis），而且当细胞处于锚定不依赖条件下时，IGF-IR的保护作用更为显著。在第二个模型中，我们将使用一系列小鼠造血细胞，在IGF-IR信号通路方面具有独特特征的32D细胞。此外，利用IGF- 1诱导造血细胞分化这一令人兴奋的新发现，我们将探索IGF系统中分化与凋亡之间的关系，以及Bcl-2家族蛋白如何调节分化。我的项目与其他3个项目在靶点和机制上都有明显的联系，并依赖于与Bruno Calabretta （32D细胞，分化）和Carlo Croce （Bcl-2蛋白家族）的严格合作。我已经与Emad Alnemri进行了合作，当我们必须确定半胱天酶在IGF-IR的抗凋亡作用中的作用时，这种合作将得到更新。这些研究，虽然是基本性质的，但可能会导致（事实上，他们已经这样做了）实际应用，特别是在癌症领域。

The aims of this project are to define the relationships between two major players in apoptosis, the type 1 insulin-like growth factor receptor (IGF- IR) and the Bcl-2 family of proteins, especially Bcl-Xl and Bad. Preliminary results from our laboratory and from the literature indicate that there is a connection between theses two systems and we intend to explore the mechanism(s) by which the IGF-IR and these proteins modulate each other in the apoptotic process. We will focus on two different systems, both of which have their advantages and disadvantages. In the first model, we will use mouse embryo fibroblasts (MEF) in conditions of anchorage- independence, because cells denied attachment to a substratum are often more susceptible to apoptosis (anoikis) than cells in monolayer cultures, and because the protective effect of the IGF-IR is more striking when the cells are in conditions of anchorage independence. In the 2nd model, we will use a line of murine hemopoietic cells, 32D cells that have unique characteristics in regard to the signaling pathway of the IGF-IR. In addition, taking advantage of a new and exciting discovery, the induction by IGF-I of differentiation in hemopoietic cells, we will explore the relationship between differntiation and apoptosis in the IGF system, and how proteins of the Bcl-2 family may modify differentiation. My project is clearly related to the other 3 projects, both in terms of targets and mechanisms, and depends on a strict collaboration with Bruno Calabretta (32D cells, differentiation) and Carlo Croce (for the Bcl-2 family of proteins). I have already had a collaboration with Emad Alnemri, and this interation will be renewed when we will have to define the role of caspases in the anti=apoptotic effects of the IGF-IR. These investigations, while of a basic nature, could lead (as, in fact, they already have) to practical applications, especially in the field of cancer.