Protection Against Apoptosis by Scatter Factor

描述(申请人提供)：背景：分散系数(SF) (肝细胞生长因子)刺激细胞运动、侵袭、上皮 通过其受体酪氨酸的形态发生、肿瘤发生和血管形成 激酶c-Met。SF和c-Met在乳腺癌中的表达增加 进展和高水平的SF与侵袭、血管生成、 预后不良。SF保护上皮细胞和乳腺癌细胞免受 细胞凋亡和对DNA损伤的抵抗力。初步研究：在 初期，我们发现：1)SF保护涉及来自 C-Met-&gt；p21Ras/PI3激酶-&gt；c-Akt/pak1-&gt；叉头FKHR；2) Grb2相关结合子GAB1，一种转导上皮细胞的适配器 形态发生，抑制c-Akt上游的这一途径；以及3)细胞凋亡 抑制部分发生在线粒体和半胱氨酸天冬氨酸酶的上游。 激活。利用cdna微阵列分析，我们确定了可能 有助于SF对拓扑异构酶II抑制剂阿霉素的保护作用： 例如，PKD1(多囊蛋白)、51C(肌醇5-磷酸酶)、TOPBP1(a 拓扑异构酶II结合蛋白)和CIP4(一种与镉42相互作用的蛋白)。 假设：SF通过一种特定的分子保护乳腺癌细胞免受DNA损伤 受GAB1和信号负性调控的c-Met信号通路 这会导致几个新基因的表达发生变化。目标： 我们建议：1)描绘c-Met信号的上游通路 乳腺癌细胞中的细胞存活，包括c-Akt和 GAB1和几种信号转导磷酸酶的抑制作用；2)阐明 DNA损伤诱导的线粒体前凋亡信号转导事件及其机制 他们被SF阻止的机制(S)，并确定了 凋亡抑制蛋白(IAPs)和SMAC在SF细胞保护中的作用 确定新的下游基因在SF对几种疾病的保护作用 DNA损伤的类型。意义：这些发现将提供新的见解 SF如何作为乳腺癌的肿瘤生存因子发挥作用。他们可能会 确定新的分子靶点以设计战略 肿瘤的放射/化学增敏和化学预防。因为SF可能会改善 某些形式的器官损伤，了解它是如何抑制细胞凋亡的也可能 为治疗发育性、炎症性或中毒性提供新的靶点 精神错乱。

DESCRIPTION (provided by applicant): Background: Scatter factor (SF) (hepatocyte growth factor) stimulates cell motility, invasion, epithelial morphogenesis, oncogenesis, and angiogenesis, via its receptor, the tyrosine kinase c-Met. SF and c-Met expression increase during breast cancer progression, and high levels of SF correlate with with invasion, angiogenesis, and poor prognosis. And SF protects epithelial and breast cancer cells against apoptosis and confers resistance to DNA damage. Preliminary Studies: During the initial period, we found that: 1) the SF protection involves signaling from c-Met -> p21Ras/PI3 kinase -> c-Akt/Pak1 -> forkhead FKHR; 2) the Grb2-associated binder Gab1, an adapter that transduces epithelial morphogenesis, inhibits this pathway upstream of c-Akt; and 3) apoptosis inhibition occurs, in part, upstream of the mitochondria and caspase activation. Using cDNA microarray analyses, we identified novel genes that may contribute to SF protection against the topoisomerase II inhibitor adriamycin: e.g., PKD1 (polycystin), 51C (an inositol 5-phosphatase), TOPBP1 (a topoisomerase II binding protein), and CIP4 (a cdc42-interacting protein). Hypothesis: SF protects breast cancer cells against DNA-damage by a specific c-Met signaling pathway that is negatively regulated by Gab1 and signaling phosphatases and that leads to altered expression of several novel genes. Aims: We propose to: 1) delineate the upstream pathways by which c-Met signals for cell survival in breast cancer cells, including the targets of c-Akt and the inhibitory roles of Gab1 and several signaling phosphatases; 2) elucidate the DNA damage-induced pre-mitochondrial apoptosis signaling events and the mechanism(s) by which they are blocked by SF, and determine the roles of inhibitor of apoptosis proteins (IAPs) and SMAC in SF cell protection; and 3) establish the roles of novel down-stream genes in SF protection against several types of DNA damage. Significance: These findings will provide new insights into how SF functions as a tumor survival factor for breast cancers. They may identify novel molecular targets for the design of strategies for radio/chemosensitization and chemoprevention of tumors. Since SF may ameliorate certain forms of organ injury, understanding how it inhibits apoptosis may also provide new targets for the treatment of developmental, inflammatory, or toxic disorders.