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细胞凋亡(apoptosis)是多细胞生物的一种基本生命活动,在机体的生长发育、免疫调节及维持内环境稳定等各方面扮演着重要的角色.遗传和生化研究表明,细胞凋亡受到复杂而精细的调控.转录水平、翻译后水平等各种层次的调控,构成了一个复杂的凋亡调控网络. 相似文献
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在人类的基因组中,超过90%的基因都会经历RNA可变剪接,可变剪接贯穿生命活动的始终.RNA剪接异常与人类的疾病密切相关,其中包括癌症.作为第二大致死因素,癌症对公共健康造成了严重的危害.在每年癌症新增及死亡病例中,肺癌均位于首位.研究发现,肺癌中存在大量剪接事件异常,可变剪接参与调控肺癌的发生和发展.在肺癌中,剪接因... 相似文献
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完整基因结构的预测是当前生命科学研究的一个重要基础课题,其中一个关键环节是剪接位点和各种可变剪接事件的精确识别.基于转录组测序(RNA-seq)数据,识别剪接位点和可变剪接事件是近几年随着新一代测序技术发展起来的新技术策略和方法.本工作基于黑腹果蝇睾丸RNA-seq数据,使用TopHat软件成功识别出39718个果蝇剪接位点,其中有10584个新剪接位点.同时,基于剪接位点的不同组合,针对各类型可变剪接特征开发出计算识别算法,成功识别了8477个可变剪接事件(其中新识别的可变剪接事件3922个),包括可变供体位点、可变受体位点、内含子保留和外显子缺失4种类型.RT-PCR实验验证了2个果蝇基因上新识别的可变剪接事件,发现了全新的剪接异构体.进一步表明,RNA-seq数据可有效应用于识别剪接位点和可变剪接事件,为深入揭示剪接机制及可变剪接生物学功能提供新思路和新手段. 相似文献
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可变剪接的生物信息数据分析综述 总被引:1,自引:0,他引:1
前体mRNA的可变剪接是扩大真核生物蛋白质组多样性的重要基因调控机制。可变剪接的错误调节可以引起多种人类疾病。由于高通量技术的发展,生物信息学成为可变剪接研究的主要手段。本文总结了可变剪接在生物信息学领域的研究方法,同时也分析并预测了可变剪接的发展方向。 相似文献
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人类基因组中可变和组成性剪接位点的预测 总被引:2,自引:0,他引:2
根据剪接位点的核酸序列保守特征,以及邻近位点的碱基组成和关联特性,结合一对可变剪接位点之间的距离参数和受体端剪接位点前30位碱基的GC和TC含量,利用结合多样性指标的二次判别方法(IDQD),预测了人类基因组中可变和组成性内含子的供体端和受体端的剪接位点,对可变的供体端和受体端剪接位点,阈值ξ选择-2时,总的预测精度分别为87.9%和89.9%,对组成性的供体端和受体端剪接位点,阈值ξ选择-1,总的预测精度分别为92.8%和94.3%. 相似文献
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细胞凋亡 (apoptosis)是多细胞生物的一种基本生命活动 ,在机体的生长发育、免疫调节及维持内环境稳定等各方面扮演着重要的角色。遗传和生化研究表明 ,细胞凋亡受到复杂而精细的调控。转录水平、翻译后水平等各种层次的调控 ,构成了一个复杂的凋亡调控网络。真核生物中 ,绝大多数蛋白质基因的初始转录产物pre mRNA必须经过剪接等加工过程 ,才能形成成熟的mRNA。可变剪接 (alternativesplicing)是指同一种pre mRNA具有多种剪接程序 ,能形成不同的mRNA。可变剪接是pre mR NA加工过… 相似文献
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mRNA的可变剪接(alternative splicing)是一种由一个mRNA前体(pre-mRNA)通过不同的剪接方式产生多个mRNA变异体(variants)的RNA加工过程。在过去很长一段时间里,人们认为mRNA剪接过程是独立于转录过程的一个转录后RNA加工过程。然而,越来越多的实验证明mRNA剪接在很大程度上是与转录偶联发生的。因此,剪接调控会受到与转录相关因素的调控。本文将对染色质与mRNA剪接调控的相关性和染色质结构调控可变剪接的分子机制进行阐述。 相似文献
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真核基因可变剪接研究现状与展望 总被引:2,自引:0,他引:2
mRNA前体(pre-mRNA)的可变剪接是控制基因表达和产生蛋白质多样性的重要机制,是功能基因组时代的研究重点之一。生物信息学在识别可变剪接基因及其结构、分析可变剪接的功能和调控方式等方面具有重要作用。除了耗时的实验研究,识别可变剪接基因及其结构主要通过EST、mRNA等转录数据与基因组序列进行比对,获得同一基因的不同结构方式。分析蛋白质产物可对可变剪接的功能进行预测;潜在调控元件的统计分析则可为可变剪接调控机制的研究提供必要的数据。转录数据的时空信息以及比较基因组学对理解可变剪接信息的精确调控将提供重要资料。可变剪接及其调控机制的深入研究将为基因组和蛋白质组之间的对接提供重要的桥梁。 相似文献
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Ermakov A. M. Gritsyna Yu. V. Belova S. P. Nemirovskaya T. L. Shenkman B. S. Vikhlyantsev I. M. 《Human physiology》2021,47(4):391-397
Human Physiology - Changes in titin alternative splicing in the rat soleus after seven-day gravitational unloading (the hindlimb unloading model) were studied by long-fragment PCR and nanopore... 相似文献
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Ping Liao Dejie Yu Zhenyu Hu Mui Cheng Liang Jue Jin Wang Chye Yun Yu Gandi Ng Tan Fong Yong Jia Lin Soon Yeow Leng Chua Tuck Wah Soong 《The Journal of biological chemistry》2015,290(14):9262-9272
L-type Cav1.2 Ca2+ channel undergoes extensive alternative splicing, generating functionally different channels. Alternatively spliced Cav1.2 Ca2+ channels have been found to be expressed in a tissue-specific manner or under pathological conditions. To provide a more comprehensive understanding of alternative splicing in Cav1.2 channel, we systematically investigated the splicing patterns in the neonatal and adult rat hearts. The neonatal heart expresses a novel 104-bp exon 33L at the IVS3-4 linker that is generated by the use of an alternative acceptor site. Inclusion of exon 33L causes frameshift and C-terminal truncation. Whole-cell electrophysiological recordings of Cav1.233L channels expressed in HEK 293 cells did not detect any current. However, when co-expressed with wild type Cav1.2 channels, Cav1.233L channels reduced the current density and altered the electrophysiological properties of the wild type Cav1.2 channels. Interestingly, the truncated 3.5-domain Cav1.233L channels also yielded a dominant negative effect on Cav1.3 channels, but not on Cav3.2 channels, suggesting that Cavβ subunits is required for Cav1.233L regulation. A biochemical study provided evidence that Cav1.233L channels enhanced protein degradation of wild type channels via the ubiquitin-proteasome system. Although the physiological significance of the Cav1.233L channels in neonatal heart is still unknown, our report demonstrates the ability of this novel truncated channel to modulate the activity of the functional Cav1.2 channels. Moreover, the human Cav1.2 channel also contains exon 33L that is developmentally regulated in heart. Unexpectedly, human exon 33L has a one-nucleotide insertion that allowed in-frame translation of a full Cav1.2 channel. An electrophysiological study showed that human Cav1.233L channel is a functional channel but conducts Ca2+ ions at a much lower level. 相似文献
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Joseph T. Roland Lynne A. Lapierre James R. Goldenring 《The Journal of biological chemistry》2009,284(2):1213-1223
Rab proteins influence vesicle trafficking pathways through the assembly of
regulatory protein complexes. Previous investigations have documented that
Rab11a and Rab8a can interact with the tail region of myosin Vb and regulate
distinct trafficking pathways. We have now determined that a related Rab
protein, Rab10, can interact with myosin Va, myosin Vb, and myosin Vc. Rab10
localized to a system of tubules and vesicles that have partially overlapping
localization with Rab8a. Both Rab8a and Rab10 were mislocalized by the
expression of dominant-negative myosin V tails. Interaction with Rab10 was
dependent on the presence of the alternatively spliced exon D in myosin Va and
myosin Vb and the homologous region in myosin Vc. Yeast two-hybrid assays and
fluorescence resonance energy transfer studies confirmed that Rab10 binding to
myosin V tails in vivo required the alternatively spliced exon D. In
contrast to our previous work, we found that Rab11a can interact with both
myosin Va and myosin Vb tails independent of their splice isoform. These
results indicate that Rab GTPases regulate diverse endocytic trafficking
pathways through recruitment of multiple myosin V isoforms.Eukaryotic cells are comprised of networks of highly organized membranous
structures that require the efficient and timely movement of diverse
intracellular proteins for proper function. Molecular motors provide the
physical force needed to move these materials along microtubules and actin
microfilaments. Unconventional myosin motors, such as those belonging to
classes V, VI, and VII, have roles in the trafficking and recycling of
membrane-bound structures in eukaryotic cells
(1) and are recruited to
discrete vesicle populations. Myosin VI is involved in clathrin-mediated
endocytosis (2), whereas myosin
VIIa participates in the proper development of stereocilia of inner ear hair
cells and the transport of pigment granules in retinal pigmented epithelial
cells (3,
4). Similarly, the three
members of vertebrate class V myosins, myosin Va, myosin Vb, and myosin Vc,
are required for the proper transport of a wide array of membrane cargoes,
such as the melanosomes of pigment cells, synaptic vesicles in neurons, apical
recycling endosomes in polarized epithelial cells, and bulk recycling vesicles
in non-polarized cells (5).Members of the Rab family of small GTPases regulate many cellular systems,
including membrane trafficking
(6,
7). Certain Rab proteins
associate with and regulate the function of class V myosins. Rab27a, in a
complex with the adaptor protein melanophilin/Slac2-a, is required to localize
myosin Va to the surface of melanin-filled pigment granules in vertebrates
(8-10),
whereas Rab27a and Slac2-c/MyRIP associate with both Myosin Va and myosin VIIa
(3,
11). Rab11a, in a complex with
its adaptor protein Rab11-FIP2, associates with myosin Vb on recycling
endosomes
(12-14)
where the tripartite complex regulates the recycling of a variety of cargoes
(15-19).
In addition, Rab8a associates with both myosin Vb
(20) and myosin Vc
(21) as part of the
non-clathrin-mediated tubular recycling system
(20). Recently, Rab11a has
also been shown to associate with myosin Va in the transport of AMPA receptors
in dendritic spines (22),
contributing to the model of myosin V regulation by multiple Rab proteins.Previous investigations have documented alternative splicing of myosin Va
in a tissue-specific manner
(23-28).
Alternate splicing occurs in a region lying between the coiled-coil region of
the neck of the motor and the globular tail region. Three exons in particular
are subject to alternative splicing: exons B, D, and F
(23-25).
Exon F is critical for association with melanophilin/Slac2 and Rab27a
(8,
9,
29,
30). Additionally, exon B is
required for the interaction of myosin Va with dynein light chain 2 (DLC2)
(27,
28). Currently no function for
the alternatively spliced exon D has been reported. Similar to myosin Va,
myosin Vb contains exons A, B, C, D, and E, whereas no exon F has yet been
identified in myosin Vb (Fig.
1A). In addition, exon B in myosin Vb does not resemble
the dynein light chain 2 (DLC2) binding region in myosin Va
(27,
28), and therefore, it likely
does not interact with DLC2. On the other hand, exon D is highly conserved
among Myosin Va, myosin Vb, and myosin Vc, suggesting a common function in
these molecular motors.Open in a separate windowFIGURE 1.Tissue distribution of human myosin Va and myosin Vb splice
isoforms. A, schematic of the alternative exon organization in
the tails of myosin Va and myosin Vb. It is known that exons B, D, and F are
subject to alternative splicing in myosin Va, whereas there is only evidence
that exon D is alternatively spliced in myosin Vb, which does not contain exon
F. B, alignment of exon D sequences from mouse and human myosin V''s.
myosin Va and myosin Vb both contain exon D (amino acids 1320-1346 of myosin
Va and 1315-1340 of myosin Vb), whereas myosin Vc contains an exon D-like
region (amino acids 1124-1147 of human myosin Vc) that is not known to be
alternatively spliced. Alignment of the exon D regions from all three motors
reveals a high degree of homology, especially in the center of the exon.
Asterisks indicate amino acid identities. C, PCR-based
analysis of human tissue panels reveals the alternative splicing pattern of
exon D in myosin Va and myosin Vb. Primers flanking the region encoding exon D
for both motors were used to amplify cDNA from human MTC™ panels
(Clontech). cDNA amplified from HeLa cell RNA as well as myosin Va and myosin
Vb tail constructs were used as positive controls. Variants expressing exon D
(upper bands) and lacking exon D (lower bands) were visible.
Per., peripheral; Pos., positive.Here we report that Rab10, a protein related to Rab8a and thought to have
similar function
(31-35),
localizes to a system of tubules and vesicles overlapping in distribution with
Rab8a in HeLa cells. Utilizing dominant-negative myosin V tail constructs, we
show that Rab8a and Rab10 can interact with Myosin Va, myosin Vb, and myosin
Vc in vivo. In addition, we have determined that the alternatively
spliced exon D in both myosin Va and myosin Vb is required for interaction
with Rab10. In contrast to our previous findings, we demonstrate that Rab11a
is able to interact with both myosin Va and myosin Vb tails in an exon
independent-manner. These results reveal that multiple Rab proteins
potentially regulate all three class V myosin motors. 相似文献