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期是内部和环境信号与细胞周期装置整合的主要间隔。未能对这些信号作出反应可能导致增殖缺陷，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协调调节一个大家族的G1特异性基因。该家族的基因编码许多细胞周期调节因子，包括促进细胞周期早期阶段进展的G1和S期细胞周期蛋白。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方式。在酵母中，G1特异性转录程序由G1细胞周期蛋白相关的细胞周期蛋白依赖性蛋白激酶CIn 3/CDK激活，CIn 3/CDK通过未知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期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的新型调节剂以及通过理解CIn/CDK与转录调节剂的相互作用来实现。在具体目标1和2中，我们建议进一步表征Whi 5，我们最近将其描述为CIn 3/CDK拮抗的SBF依赖性转录的负调节因子。在具体目标3中，我们提出鉴定和表征SBF和MBF的新型调节剂。最后，在具体目标4中，我们建议建立RSC染色质重塑复合物和G1细胞周期蛋白之间相互作用的生物学相关性。我们希望，完成拟议的研究将提供一个广泛的理解与转录机制的细胞周期调控装置的协调，从而提高我们的理解控制细胞增殖在正常和疾病状态。

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.