Studies of Normal and Neoplastic Prostate

描述（由申请人提供）：多年来，我们一直专注于研究蛋白激酶CK2的基本功能生物学，特别是其在前列腺癌病理生物学中的作用。CK2是一种普遍存在的高度保守的多功能蛋白丝氨酸/苏氨酸激酶，长期以来与细胞生长和增殖有关。它在癌症中的重要性通过它在包括前列腺癌在内的所有已被检查的癌症中放松管制而得到强调。我们的范式转换发现，CK2也可以抑制细胞凋亡，这首次表明CK2与肿瘤发生之间存在重要的新联系，因为细胞凋亡的失调（特别是在前列腺癌中）是癌症表型的一个关键特征。我们的工作假设是CK2在正常和异常的前列腺生长控制中起着至关重要的作用，其失调通过影响细胞生长、凋亡和存活与肿瘤发生密切相关。我们的长期目标是研究CK2信号在细胞生长和细胞凋亡抑制中的作用机制，并在针对前列腺癌的转化研究中利用CK2功能病理生物学的关键特征。为此，我们建议(a)研究CK2转运到核基质的机制；(b)探讨CK2抑制细胞凋亡的机制；(c)利用其下调作为一种潜在的治疗方式；(d)靶向其过表达，生成新的前列腺癌转基因小鼠模型。综上所述，我们对CK2功能生物学与前列腺癌生物学的研究是一个重要而独特的研究领域。同样重要的是将这些知识应用于开发新的转基因小鼠模型和前列腺癌的新治疗方式。前列腺癌是美国男性癌症相关死亡的主要原因，这一事实强调了这些研究的相关性

DESCRIPTION (provided by applicant): Over the years, we have focused on investigation of the fundamental functional biology of protein kinase CK2 with a specific view to its role in the pathobiology of prostate cancer. CK2 is a ubiquitous highly conserved multifunctional protein ser/thr kinase that has long been implicated in cell growth and proliferation. Its importance in cancer is emphasized by its deregulation in all the cancers that have been examined, including prostate cancer. Our paradigm-shifting discovery that CK2 can also suppress apoptosis suggests, for the first time, an important new link between CK2 and oncogenesis since deregulation of apoptosis (especially in prostate cancer) is a key feature of cancer phenotype. Our working hypothesis is that CK2 plays crucial roles in normal and abnormal prostatic growth control, and its deregulation is critically associated with oncogenesis through its impact on cell growth, apoptosis, and survival. Our long-term goals are to investigate the mechanisms involved in CK2 signaling in cell growth and suppression of apoptosis, and to exploit the key features of CK2 functional pathobiology in translational studies targeted to prostate cancer. To this end, we propose (a) to investigate the mechanisms involved in shuttling of CK2 to the nuclear matrix; (b) to examine the mechanisms by which CK2 suppresses apoptosis; (c), to exploit its downregulation as a potential therapeutic modality; and (d) to target its overexpression for generating a new transgenic mouse model of prostate cancer. In summary, our studies on CK2 functional biology with reference to prostate cancer biology represent an important and unique area of investigation. Also significant is the application of this knowledge to the development of a new transgenic mouse model and a new therapeutic modality for prostate cancer. The relevance of these studies is underscored by the fact that prostate cancer is a leading cause of cancer-related deaths in men in the U.S.A.