A MECHANISM FOR C-SRC ACTIVATION IN OVARIAN CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们发现，在卵巢肿瘤中，CSRC和CSRC的结合伙伴和激活因子AFAP-110这两种蛋白的表达增加在分化和浸润性卵巢癌中同时发生，并且这两种蛋白在同一肿瘤细胞中过表达。由于已知CSRC在卵巢癌中被激活，并可促进肿瘤的侵袭或对化疗的抵抗，伴随的CSRC激活蛋白的过度表达提示CSRC激活的可能机制。AFAP-110将激活CSRC以响应输入信号，进而引导肿瘤变得侵袭性。有趣的是，我们在卵巢肿瘤细胞中发现了AFAP-110的一个多态变体，称为AFAP-110403C，当 与AFAP-110不同，过度表达可以独立于输入信号激活CSRC。识别一种蛋白质的多态变体(AFAP-110403C)是一项新颖和创新的发现，该变体在高表达的条件下，相对于更常见的表达的对应物(AFAP-110)，具有更强的促进信号的能力，从而指导肿瘤的进展。因此，我们假设AFAP-110403C和CSRC(共同)的表达增加将导致CSRC激活，并促进卵巢癌后续的肿瘤侵袭。在本提案中，我们将解决AFAP-110403C能够独立指导中国证监会激活的机制

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have discovered that increased expression of two proteins in ovarian tumors, cSrc and a binding partner and activator for cSrc called AFAP-110, occur together in differentiated and invasive ovarian carcinomas, and that over expression of both these proteins occur in the same tumor cells. As cSrc is known to be activated in ovarian cancer and can promote either invasion or resistance to chemotherapy, the concomitant over expression of a cSrc activating protein indicates a possible mechanism for cSrc activation. AFAP-110 will activate cSrc in response to input signals, which in turn directs tumors to become invasive. Interestingly, we identified in ovarian tumor cells a polymorphic variant of AFAP-110, called AFAP-110403C, which when overexpressed, can activate cSrc independent of an input signal, unlike AFAP-110. It is both a novel and innovative finding to identify a polymorphic variant of a protein (AFAP-110403C) that, under conditions of high expression, has an increased capacity to promote signals that direct tumor progression relative to the more commonly expressed counterpart, (AFAP-110). Thus, we hypothesize that increased expression of both AFAP-110403C and cSrc (together) will result in cSrc activation and promote subsequent tumor invasion in ovarian cancer. In this proposal, we will address the mechanism by which AFAP-110403C is able to independently direct cSrc activation