Inhibition of retinoblastoma protein degradation by interaction with the serpin PAI-2 via a novel consensus motif

纤溶酶原激活物抑制物-2(PAI-2)此前已被证明可以抑制细胞外参与血液凝结和细胞迁移的酶的活性。我们发现这一活性可能不是PAI-2的主要作用。PAI-2在细胞内还具有保护和增加一种重要的肿瘤抑制蛋白(Rb)活性的功能，该蛋白称为视网膜母细胞瘤肿瘤抑制蛋白(Rb)。Rb参与许多细胞功能，如细胞死亡、细胞分化、细胞生长，以及最重要的是预防癌症的发展。RB受到几种病毒的攻击和破坏，导致细胞癌变。这项拨款旨在充分了解PAI-2如何保护RB并与其相互作用。我们已经在RB上找到了PAI-2结合的新位点。该位点也被细胞中的其他蛋白质以及致病病毒蛋白质所使用。这些蛋白质的例子是BRCA1，一种与乳腺癌发展有关的蛋白质，以及EBNA6，一种来自爱泼斯坦-巴尔病毒的蛋白质，会导致腺热和肿瘤。我们还发现，并寻求进一步探索，PAI-2如何逆转导致人类乳头瘤病毒蛋白的宫颈癌的活性。虽然在早期阶段，这些研究可能会导致基于PAI-2的新治疗药物的开发，用于治疗由HPV引起的各种类型的癌症或疣。分析PAI-2在细胞内的活性将有助于理解关于PAI-2的许多令人困惑的科学文献，并将更好地理解PAI-2在炎症、细胞分化、伤口愈合和癌症中的作用。例如，人们早就知道，在癌症肿瘤中PAI-2的存在与更好的预后有关，这一活动现在可以通过PAI-2与Rb的相互作用来理解。这一新的认识可能导致基于PAI-2的癌症预后检测的发展。

Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cell differentiation, cell growth, and most importantly prevention of cancer development. Rb is attacked and destroyed by several viruses which causes cells to become cancerous. This grant seeks to fully understand how PAI-2 protects and interacts with Rb. We have already found a new site on Rb to which PAI-2 binds. This site is also used by other proteins in the cell as well as disease causing virus proteins. Examples of these proteins are BRCA1, a protein involved in breast cancer development, and EBNA6, a protein from Epstein Barr virus that causes glandular fever and tumours. We have also found, and seek to explore further, how PAI-2 reverses the activities of the cervical cancer causing proteins of the human papilloma virus. Although at an early stage, these studies may lead to the development of new therapeutic drugs based on PAI-2 for the treatment of various types cancers or warts caused by HPV. Analysing the activity of PAI-2 inside cells will have implications for understanding much of the confusing scientific literature on PAI-2 and will provide a better comprehension of the role of PAI-2 in inflammation, cell differentiation, wound healing and cancer. For example it has long been known that the presence of PAI-2 in cancerous tumours is linked with a better prognosis, an activity that can now be understood in terms of the PAI-2 interaction with Rb. This new understanding may lead to the development of PAI-2 based prognostic assays for cancer.