IDENT AND POST-TRANSLATIONAL MODIFICATION OF MITOTIC REGULATORY PROTEINS

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。 Polo样激酶(PLK)家族由4个密切相关的蛋白(PLK1-4)组成，它们在细胞周期控制、分化以及调节遗传毒性和氧化应激反应中具有多种功能。PLK家族成员的差异表达在许多乳腺癌组织和细胞系中观察到，并在暴露于乳腺癌治疗后，如电离辐射。PLK1和PLK3在癌症中似乎具有相反的作用；PLK1过表达通过覆盖细胞周期检查点控制、促进细胞增殖和促进转移而导致恶性表型，而PLK3具有明显的肿瘤抑制功能。鉴于PLK1的过度表达可以作为癌症的预后指标，并参与许多癌症促进细胞功能的作用，它已成为小分子抑制剂单独或与其他乳腺癌治疗联合使用的有力靶点。然而，大多数已发现的PLK1抑制剂也有效地抑制了PLK3，并可能对PLK3阳性的乳腺肿瘤产生负面影响，因为PLK3的激活在P53介导的细胞凋亡中起着作用。个别肿瘤可能会表现出PLK激活物(如Aurora-A)和相互作用蛋白(如介导PLK依赖功能的P53)的丰度和/或功能的变化。因此，针对PLK的上游和/或下游效应因子的替代策略可能是PLK信号的有效抑制剂，治疗可以更好地定制，不仅反映肿瘤的PLK状态，而且反映整个PLK信号通路。我们假设，在正常细胞和癌细胞以及暴露于电离辐射和其他类型的癌症治疗等刺激前后，将存在主要的含有特定PTM和结合伙伴的蛋白质复合体。识别这些上下文相关的生物特征可以作为新的诊断标记，突出它们产生的信号通路，并有助于开发定制的癌症治疗方法。为了验证我们的假设，我们提出了以下特定的目标，专注于PLK1和PLK3蛋白复合体，它们在增殖和DNA损伤反应中扮演相反的角色。

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. The Polo like kinase (PLK) family is comprised of 4 closely related proteins (PLK1-4) with multiple functions in cell cycle control, differentiation, and regulation of genotoxic and oxidative stress responses . Differential expression of PLK family members is observed in many breast cancer tissues and cell lines and following exposure to breast cancer treatments such as ionizing radiation. PLK1 and PLK3 in particular appear to have opposing roles in cancer; PLK1 overexpression contributes to malignant phenotypes by overriding cell cycle checkpoint controls, increasing cell proliferation, and contributing to metastasis while PLK3 has an apparent tumor suppressor function. Given that PLK1 overexpression can serve as a prognostic indicator of cancer and is involved in many cancer promoting cell functions, it has emerged as a strong target for small molecule inhibitors given alone or in conjunction with other breast cancer treatments. However, most of the identified PLK1 inhibitors effectively inhibit PLK3 as well and could have a negative impact on PLK3 positive breast tumors since PLK3 activation plays a role in p53 mediated apoptosis. Individual tumors will likely exhibit alterations in the abundance and/or function of PLK activators such as Aurora-A and interacting proteins such as p53 that mediate PLK dependent functions. Therefore, alternative strategies that target upstream kinases and/or downstream effectors of PLKs could be effective inhibitors of PLK signaling and treatments could be better tailored to reflect not only the PLK status of tumors but also the overall PLK signaling pathway. We hypothesize that there will be predominant protein complexes containing specific PTMs and binding partners present in normal vs cancer cells and before and after exposure to stimuli such as ionizing radiation and other types of cancer treatments. Identification of these context dependent biosignatures could serve as novel diagnostic markers, highlight the signaling pathways responsible for their generation, and aid in developing tailored cancer therapies. To test our hypothesis, we propose the following specific aims focused on PLK1 and PLK3 protein complexes with opposing roles in proliferation and DNA damage responses.