HIF的多重化增强了含有缺氧辅助序列的目标基因的转录
Tamara Rosell-Garcia1, Sergio Rivas-Muñoz1, Koryu Kin2
1Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad Autónoma de Madrid (U.A.M.), Madrid, Spain.
概括
缺氧诱导因子 (HIF) 的活性被一种新的HIF辅助序列 (HAS) 增强. 这种HAS基因使HIF蛋白多元化成为可能,促进了参与发育的低氧调节基因的转录反应.
科学领域:
- 细胞和分子生物学 细胞和分子生物学
- 基因规则 基因规则
- 缺氧信号传递 缺氧信号传递
背景情况:
- 缺氧诱导因子 (HIF) 对于细胞适应低氧的情况至关重要.
- HIF作为异构体起作用,与特定的DNA动机结合,以调节基因表达.
- 已知与HIF结合位点相邻的HIF辅助序列 (HAS) 可增强转录,但其机制尚不清楚.
研究的目的:
- 调查HAS元素对低氧反应的功能性贡献.
- 阐明HAS增强HIF转录活性的机制.
- 确定HAS在调节低氧反应基因中的作用.
主要方法:
- 使用了NIH/3T3小鼠胚胎纤维细胞和HEK293人类胚胎细胞.
- 采用HIF过度表达实验来研究HAS动机的功能.
- 分析了含有转录因子结合部位和基因本体学的HAS/HIF动机的基因促进剂.
- 研究了HIF1β亚单元的Fα螺旋在异构体相互作用中的作用.
主要成果:
- 哈斯基因对最大的缺氧诱导基因表达至关重要.
- 协同使用的HAS/HIF元素促进了HIF蛋白质的多重化 (例如,四聚体),增强了转录的潜能.
- HIF1β PAS-B 域的 Fα 螺旋对于稳定 HIF 异构体之间的相互作用至关重要.
- 具有HAS/HIF基因的人类基因显示出较高的缺氧反应能力,并在发育过程中得到丰富.
结论:
- HAS元件为低氧/HIF信号提供了一个额外的监管层.
- 在含有 HAS 的元素上 HIF 蛋白质的多元化显著放大了对缺氧的转录反应.
- 在与组织形成和发育相关的基因中,HAS/HIF基因普遍存在,突出显示了它们的生物学重要性.
相关概念视频
01:24Regulation of Angiogenesis and Blood Supply
2.6K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.6K
02:23Master Transcription Regulators
6.9K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.9K
01:30General Transcription Factors
5.4K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
5.4K
01:23Hypoxia
1.1K
Hypoxia is a medical condition characterized by an inadequate oxygen supply to body tissues. It typically manifests as a bluish discoloration of the skin and mucosae, especially in fair-skinned individuals, when hemoglobin (Hb) saturation drops below 75%.
Types of Hypoxia
There are four primary types of hypoxia, each resulting from a different cause:
1. Anemic hypoxia: This type occurs due to insufficient oxygen delivery caused by a lack of red blood cells (RBCs) or RBCs with abnormal or...
Types of Hypoxia
There are four primary types of hypoxia, each resulting from a different cause:
1. Anemic hypoxia: This type occurs due to insufficient oxygen delivery caused by a lack of red blood cells (RBCs) or RBCs with abnormal or...
1.1K
02:36RNA Polymerase II Accessory Proteins
9.2K
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
9.2K
02:53Adaptive Mechanisms in Cancer Cells
5.8K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.8K