Regulation of G1-Specific Gene Expression in Yeast

描述（由申请人提供）：在大多数真核细胞中，G1期是细胞周期仪器整合内部和环境信号的主要间隔。如果不能对这些信号作出反应，就会导致增殖缺陷，在后生动物中，可能包括恶性肿瘤甚至死亡。控制细胞周期进程的主要控制之一是通过一个大的g1特异性基因家族的协调调节。该家族的基因编码许多细胞周期调节因子，包括G1期和S期周期蛋白，促进细胞周期早期阶段的进展。因此，调节g1特异性基因的表达是协调调节许多过程的有效途径。在酵母中，G1特异性转录程序由G1周期蛋白相关的周期蛋白依赖蛋白激酶（CIn3/CDK）激活，该激酶通过未知的机制激活启动子相关的SBF和MBF转录因子。本研究的目的是了解g1特异性基因表达的调控，以及转录调控与细胞周期蛋白/CDK机制的整合。这将通过发现和表征SBF和MBF的新调节因子以及了解CIn/CDK与转录调节因子的相互作用来实现。在Specific Aims 1和2中，我们提出进一步表征wh5，我们最近将其描述为被CIn3/CDK拮抗的sbf依赖性转录的负调节因子。在具体目标3中，我们建议识别和表征SBF和MBF的新调节器。最后，在Specific Aim 4中，我们提出建立RSC染色质重塑复合体与G1细胞周期蛋白相互作用的生物学相关性。我们希望这项研究的完成将为细胞周期调控装置与转录机制的协调提供一个广泛的理解，从而增强我们对正常和疾病状态下细胞增殖控制的理解。

DESCRIPTION (provided by applicant): In most eukaryotic cells, G1 phase is the primary interval for integration of internal and environmental signals with the cell cycle apparatus. Failure to respond to those signals can lead to defects in proliferation that, in metazoans, may include malignancy and even death. One of the primary controls governing cell cycle progression is via coordinate regulation of a large family of G1-specific genes. Genes of that family encode numerous cell cycle regulators including G1 and S phase cyclins that promote progression through early stages of the cell cycle. Consequently, modulating expression of G1-specific genes is an efficient way of coordinately regulating many processes. In yeast, the G1-specific transcription program is activated by the G1 cyclin-associated cyclin dependent protein kinase, CIn3/CDK that activates promoter-associated SBF and MBF transcription factors via an unknown mechanism. The goal of the proposed research is understand the regulation G1-specific gene expression and the integration of transcriptional regulation with the cyclin/CDK machinery. This will be accomplished through discovery and characterization of novel regulators of SBF and MBF and by understanding the interaction of CIn/CDK with regulators of transcription. In Specific Aims 1 and 2, we propose to further characterize Whi5, which we recently described as negative regulator of SBF-dependent transcription antagonized by CIn3/CDK. In Specific Aim 3, we propose to identify and characterize novel regulators of SBF and MBF. Finally, in Specific Aim 4, we propose to establish the biological relevance of the interaction between the RSC chromatin-remodeling complex and G1 cyclins. We are hopeful that completion of the proposed research will provide a broad understanding of coordination of the cell cycle regulatory apparatus with the transcriptional machinery, thereby, enhancing our understanding of the control of cell proliferation in both normal and disease states.