p63与肿瘤发生调控网络研究进展

p63是p53家族成员之一,由于启动子和选择性剪切的不同,编码两类功能相异的蛋白异构体(TAp63与△Np63),在多种鳞状上皮源性肿瘤中发生表达改变,与肿瘤发生发展关系密切。p63作为转录因子通过调节下游靶基因及激活多种信号通路而发挥作用。由于p63的两类异构体功能相悖,当△Np63-TAp63表达动态平衡偏倚时,可引起细胞生物学行为的改变,但调控关系复杂,许多机制并未明了。该文结合当前研究进展,对p63各亚型的结构特点、活性调节及其参与细胞增殖、分化、凋亡和黏附迁移等几方面的调控作用作一综述,并对其未来研究方向进行了展望。     

雌激素受体参与疼痛调控的研究进展

雌激素受体属转录因子核受体超家族成员。雌激素受体的两个亚型ERα和ERβ都有类似于核受体超家族成员的调节结构,介导雌激素参与生理和病理过程中的多种效应。ERα和ERβ广泛分布于神经系统中疼痛调节相关的区域,大量动物实验及临床研究资料证实ERα和ERβ参与急、慢性疼痛的调控。本文拟对雌激素受体的特性及其在疼痛调控中的作用予以阐述。     

TFIID在配子发生和早期胚胎发育过程中的作用

配子发生以及胚胎早期发育过程受严格且有序的基因表达调控。多种转录因子与靶基因结合,激活基因的时空特异性表达,实现受精卵全能性的获得,完成母型基因组转录调控向合子基因组转录调控的转变以及随后胚胎细胞的分化调节。研究表明,TFIID转录因子家族在这些关键阶段起重要作用,在基因转录调节的起始阶段,TFIID转录因子家族成员作为通用转录因子被招募到靶基因的启动子上,与其他转录因子共同形成转录前起始复合物,起始转录。该文总结了TFIID转录因子的结构、作用方式,以及在配子发生和早期胚胎发育中的调控作用。     

ERα的辅调节因子与乳腺癌关系的研究进展

雌激素受体α（estrogen receptorα,ERα）是配体依赖的转录因子,属于核受体超家族成员。ERα介导转录的经典途径是与雌激素结合后作用于靶基因启动子区的雌激素反应元件（estrogen response element,ERE）,进而诱导靶基因转录。ERα招募辅调节因子（共激活子和共抑制子）参与ERα介导的基因转录调控。辅调节因子主要通过乙酰化、磷酸化、甲基化等表观遗传机制参与转录调控,影响靶蛋白表达水平。ΕRα介导的基因转录调控在乳腺癌的增殖、分化、侵袭转移等过程中发挥重要作用。综述在ERα介导的基因转录调控中几类辅调节因子对乳腺癌发生发展的影响。     

缺氧诱导因子-1和缺氧诱导因子-2：结构、功能及调节

缺氧诱导因子-1（HIF-1）和缺氧诱导因子-2（HIF-2）是细胞应对缺氧时关键的转录因子,在生物体生理及病理过程中有重要的作用。HIF由一个α亚基和一个β亚基组成二聚体。在蛋白水平上,HIF的稳定性及转录活性受到多种机制的调控,除为人所熟知的O2/PHDs/pVHL降解途径及FIH-1羟基化作用外,分别针对HIF-1α和HIF-2α的特异性调控机制也相继被报道。从HIF-1α和HIF-2α的蛋白结构、稳定性调控、转录激活功能以及两者在细胞代谢、肿瘤发生中的作用等方面对两者的相似性和差异性进行综述。     

调控植物种子发育的转录因子研究进展

植物种子是裸子植物和被子植物所特有的繁殖器官,也是人类赖以生存粮食的最主要来源。植物种子发育的过程包括形态发育和种子成熟,由一个复杂的转录因子网络管控,转录因子调控和监管整个发育过程。转录因子包含DNA结合区、寡聚化位点区、核定位信号区和转录调控区4个功能结构域,通过结构域与顺式元件相互作用调控基因的表达。研究表明,WOX家族调控胚芽发育,HAP3家族调控胚胎形态发生和细胞分化,MADS-box家族调控胚座和胚珠的发育,NAC家族调控胚珠珠被生长发育,b HLH家族调控种皮细胞的大小和形态,MYB家族是种皮发育的正调节因子。HAP家族成员LEC1和B3超家族的AFL亚家族成员LEC2、FUSCA3、ABI3一起互相作用形成一个调控网络,共同调控种子的成熟发育。Zinc finger超家族的Dof家族调控种子的胚乳发育、贮藏蛋白的合成及脂肪含量的变化,bZIP家族调控种子贮藏基因表达,AP2/EREBP家族调控种子体积与重量、蛋白与油类积累,WRKY家族、IKU、MINI3、SHB1基因和KLU基因调控种子体积大小。综述了植物种子发育过程中转录因子的结构和种类,分析了其作用顺序和功能,解析了种子发育的分子调控机制,展望了其研究方向和前景,以期为种子品质改良奠定理论基础和提供新的思路。     

p21WAF1／CIP1基因上游主要转录调控序列区及其相关功能

p21蛋白作为周期依赖性蛋白激酶抑制因子,调节细胞周期的进程,参与细胞生长、增殖、分化、衰老等多种活动,p21/WAF1/CIP1基因上游启动子中含有多个转录调控序列,包括p53,Sp1,Ap2,VDR及RAR,STAT,C/EBPα,β,E2A,MyoD和E2F等转录因子的顺式结合元件,在细胞的生长、分化、凋亡,衰老及疾病的发生发展中,这些转录因子通过与p21上游相应调控区相互作用,调节p21基因的表达。     

HNFlα的蛋白质复合体

肝细胞核因子1A（hepatocyte nuclear factor1A,HNFlα）是肝脏富集转录因子家族成员之一,调控多种肝脏特异基因的表达,参与维系肝脏的正常表型与功能。HNFlα与多种蛋白质相互作用,以复合体的形式发挥转录调节功能。复合体组成的动态变化在调控基因组织特异性表达、维持内环境稳定、修复组织损伤以及药物代谢中发挥了重要的作用。HNFlα的突变型改变了其在体内的相互作用网络,致使靶基因转录失调,诱发青少年发病型成人糖尿病（MODY3）。     

PU.1转录因子调控前体脂肪细胞生脂的分子机制研究进展

PU.1转录因子是保守的DNA结合蛋白Ets家族成员,因其DNA结合区识别共有序列GAGGAA,故该区又称为Ets结合区或PU.1box。PU.1主要在造血系统如髓细胞和B淋巴细胞中表达,调节关键髓系基因的转录从而调控造血系统的分化。PU.1周身敲除后,由于胎儿肝脏中缺乏B淋巴细胞和髓系细胞,导致小鼠胚胎早期死亡,表明PU.1是调控生命过程的关键转录因子。目前,在脂肪细胞中PU.1对脂肪生成作用及机制的研究报道较少。PU.1与脂肪细胞脂肪生成,与miRNAs、antisense RNA以及C/EBPα/β-PPARγ通路的调控关系将是今后研究的重点。     

植物NAC转录因子的研究进展

NAC(NAM、ATAF1、ATAF2和CUC2)转录因子是植物特有的一类转录因子,在多种陆生植物基因组中发现有超过100个成员,是植物基因组中最大的转录因子家族之一.该家族转录因子的共同特点是其N端具有保守的NAC结构域,C端则为高度变异和具有转录激活功能的调控区.具有多种生物功能NAC家族转录因子在植物生长发育、胁迫应答和激素调节等过程中具有重要作用.就植物NAC转录因子的基本结构特征和生物学功能最新研究进展进行综述.     

Ionizing radiation-induced TAp63α phosphorylation at C-terminal S/TQ motifs requires the N-terminal transactivation (TA) domain

TAp63α, a homolog of p53 and one of six alternatively spliced p63 isoforms, is a critical mediator of the ionizing radiation (IR)-induced DNA damage response in female germ cells and also tumor suppression in somatic cells. The ΔNp63α isoform, lacking the N-terminal transactivation (TA) domain, is associated with oncogenic potential. The mechanism of p63 functional regulation is not well understood. TAp63α is phosphorylated by ionizing radiation (IR)-induced DNA damage and gene transactivation is likely to be involved. Based on information gleaned from studies on p53, we explored the possibility that TAp63α S/TQ sites may be phosphorylated by IR-induced DNA damage. Our findings show a wortmanin-sensitive kinase phosphorylates TAp63α at C-terminal Ser-Gln and Thr-Gln (S/TQ) sites but not N-terminal S/TQ sites. ΔNp63α, lacking the TA domain, and TAp63γ, lacking C-terminal domains, including S/TQ sites, fail to undergo IR-induced phosphorylation. We propose a model for TA domain-dependent C-terminal phosphorylation drawing from previously described self-inactivating intramolecular interaction between N-terminal TA domain and C-terminal Transactivation Inhibitory Domain (TID) of TAp63α. A specific topology adopted only by TAp63α, but not possible for ΔNp63α or TAp63γ, may lead to TAp63α-specific kinase recruitment, phosphorylation and self-inactivation release. TID-lacking TAp63γ, like p53, is constitutively active and thus may forgo phosphorylation-dependent activation. Thus, p53 is regulated by protein stabilization and TAp63α by protein activation but both appear to involve S/TQ phosphorylation. The difference in phosphorylation potential of TAp63α and ΔNp63α may in part help explain why the two similar isoforms have diametrically opposite tumor suppression and oncogene functions, respectively.     

The Fatty Acid Synthase Gene is a Conserved p53 Family Target Gene from Worm to Human

The discovery that the p53 family consists of three members (p53, p63 and p73) in vertebrates and of a single homolog in invertebrates has raised the challenge of understanding the functions of the ancestor and how they have evolved and differentiated within the duplicated genes in vertebrates. Here, we report that the fatty acid synthase (FAS) gene, encoding for a key enzyme involved in the biogenesis of membrane lipids in rapidly proliferating cells, is a conserved target of the p53 family throughout the evolution. We show that CEP-1, the C. elegans p53 homolog, is able to bind the two p53 family responsive elements (REs) identified in the worm fasn-1 gene. Moreover, we demonstrate that fasn-1 expression is modulated by CEP-1 in vivo, by comparing wild-type and CEP-1 knockout worms. In human, luciferase and chromatin immunoprecipitation assays demonstrate that TAp73α and ΔNp63α, but not p53, TAp73β and TAp63α bind the two p53 REs of the human FASN gene. We show that the ectopic expression of TAp73β and ΔNp63α leads to an increase of FASN mRNA levels, while their silencing produces a decrease of FASN expression. Furthermore, we present data showing a correlation between ΔNp63α and FASN expression in cellular proliferation. Of relevant importance is that fasn-1 is the first CEP-1 direct target gene identified so far in C. elegans and our results suggest a new CEP-1 role in cellular proliferation and development, besides the one already described in apoptosis of germ cells. These data confirm the hypothesis that the ancestral functions of the single invertebrate gene may have been spread out among the three vertebrate members, each of them have acquired specific role in cell cycle regulation.