LSF AND MAMMALIAN CELL CYCLE PROGRESSION
LSF 和哺乳动物细胞周期进展
基本信息
- 批准号:6939078
- 负责人:
- 金额:$ 6.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-06-15 至 2005-03-31
- 项目状态:已结题
- 来源:
- 关键词:3T3 cellsDNA binding proteinDNA replicationautoradiographybiological signal transductioncell cyclecell growth regulationcyclin dependent kinaseenzyme substrategel mobility shift assaygene induction /repressionimmunoprecipitationphosphorylationpolymerase chain reactionsite directed mutagenesisthymidylate synthasetranscription factortransfectionwestern blottings
项目摘要
The growth of mammalian cells is driven by signal transduction pathways, whose targets include transcription factors that regulate expression of genes critical to cell cycle progression. At one pivotal point in late G1 phase, the restriction point, cellular signals are integrated to determine whether to replicate cellular DNA (progress to S phase) or revert to a resting state. The signalling molecules required for transit from G1 to S include both D and E cyclins complexed with cyclin-dependent kinases (CDKs). Cyclin D/CDKs phosphorylate Rb and activate members of the E2F family of transcription factors, resulting in activation of genes important for cellular DNA synthesis. Little is known, however, about the regulation of other transcription factors that activate additional components of the DNA synthesis machinery, including potential transcription factors that are targeted by cyclin E/CDK at this key point in the cell cycle. Our recent studies have shown that the mammalian transcription factor LSF plays a key role in cell cycle progression by regulating thymidylate synthase (TS) expression at the G1/S transition. Because TS is essential for cell growth, it has been a cancer chemotherapeutic target for over two decades. Likewise, as an essential regulator of TS expression, LSF may ultimately prove a valuable target for cancer therapies. The DNA-binding activity of LSF is enhanced in late G1, via the modification of pre-existing pools of nuclear LSF. In vitro, LSF is an effective substrate for cyclin E/cdk2. An understanding of the signaling pathway that regulates LSF, and the molecular mechanism by which LSF regulates TS expression may therefore illuminate novel signaling events in cell cycle progression in mammalian cells. Specifically, this proposal will address the following: 1. Is LSF phosphorylated by cyclin E/cdk2 during the late G1 phase? 2. Does phosphorylation of LSF by cyclin E/cdk2 (or other relevant modifications) alter the DNA-binding and transcriptional activities of LSF? 3. Is LSF a major target of cdk2 (or another pathway) in progression of cells into S? 4. Does LSF critically regulate genes other than TS during cell cycle progression?
哺乳动物细胞的生长是由信号转导途径驱动的,其靶标包括调节细胞周期进程关键基因表达的转录因子。在G1期晚期的一个关键点,即限制点,细胞信号被整合以决定是否复制细胞DNA(进展到S期)或恢复到静息状态。从G1转运到S所需的信号分子包括D和E细胞周期蛋白与细胞周期蛋白依赖性激酶(CDKs)的复合物。Cyclin D/CDKs磷酸化Rb并激活转录因子E2F家族成员,从而激活对细胞DNA合成重要的基因。然而,对于激活DNA合成机制的其他组分的转录因子的调控知之甚少,包括在细胞周期的这个关键点上被细胞周期蛋白E/CDK靶向的潜在转录因子。我们最近的研究表明,哺乳动物转录因子LSF通过调节G1/S过渡阶段胸腺苷酸合成酶(TS)的表达,在细胞周期进程中起关键作用。由于TS对细胞生长至关重要,它已经成为癌症化疗的靶点超过二十年。同样,作为TS表达的重要调节因子,LSF可能最终被证明是癌症治疗的一个有价值的靶点。LSF的dna结合活性在G1晚期通过对已有核LSF池的修饰而增强。在体外,LSF是cyclin E/cdk2的有效底物。因此,了解调控LSF的信号通路,以及LSF调控TS表达的分子机制,可能会阐明哺乳动物细胞周期进程中的新信号事件。具体而言,本提案将解决以下问题:细胞周期蛋白E/cdk2是否在G1期后期使LSF磷酸化?2. 细胞周期蛋白E/cdk2磷酸化LSF(或其他相关修饰)是否会改变LSF的dna结合和转录活性?3. LSF是cdk2(或其他途径)在细胞向S转变过程中的主要靶点吗?4. LSF是否在细胞周期进程中严格调节TS以外的基因?
项目成果
期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Transcription factors LSF and E2Fs: tandem cyclists driving G0 to S?
- DOI:10.4161/cc.8.14.9089
- 发表时间:2009-07-15
- 期刊:
- 影响因子:0
- 作者:Hansen U;Owens L;Saxena UH
- 通讯作者:Saxena UH
Binding of LBP-1a to specific immunoglobulin switch regions in vivo correlates with specific repression of class switch recombination.
LBP-1a 与体内特定免疫球蛋白转换区域的结合与类别转换重组的特异性抑制相关。
- DOI:10.1002/eji.200838226
- 发表时间:2009
- 期刊:
- 影响因子:5.4
- 作者:Repetny,KarenJ;Zhong,Xuemei;Holodick,NicholE;Rothstein,ThomasL;Hansen,Ulla
- 通讯作者:Hansen,Ulla
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ULLA M HANSEN其他文献
ULLA M HANSEN的其他文献
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{{ truncateString('ULLA M HANSEN', 18)}}的其他基金
MASS SPECTRAL ANALYSIS OF TRANSCRIPTION FACTOR LSF IN VITRO PHOSPHORYLATION
转录因子 LSF 体外磷酸化的质谱分析
- 批准号:
7369210 - 财政年份:2006
- 资助金额:
$ 6.85万 - 项目类别:
MASS SPECTRAL ANALYSIS OF TRANSCRIPTION FACTOR LSF IN VITRO PHOSPHORYLATION
转录因子 LSF 体外磷酸化的质谱分析
- 批准号:
7182165 - 财政年份:2005
- 资助金额:
$ 6.85万 - 项目类别:
eNOS Promoter Activation by Estrogen in Vascular Cells
血管细胞中雌激素对 eNOS 启动子的激活
- 批准号:
6837799 - 财政年份:2004
- 资助金额:
$ 6.85万 - 项目类别:
MASS SPECTRAL ANALYSIS OF TRANSCRIPTION FACTOR LSF IN VITRO PHOSPHORYLATION
转录因子 LSF 体外磷酸化的质谱分析
- 批准号:
6978458 - 财政年份:2004
- 资助金额:
$ 6.85万 - 项目类别:
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人 HMG 14 蛋白的转录诱导
- 批准号:
6386633 - 财政年份:1998
- 资助金额:
$ 6.85万 - 项目类别:
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