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PROTEIN KINASE C IN THE LENS

晶状体中的蛋白激酶 C

基本信息

批准号：
7858038
负责人：
DOLORES Jean TAKEMOTO
金额：
$ 36.64万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7858038
关键词：
Age Apoptosis Apoptotic Binding Biochemical Blindness Brain Bystander Effect Cataract Cell Differentiation process Cells Connexin 43 Connexins Crystallins Cytochromes Data Diabetes Mellitus Diabetic Retinopathy Disease Drops Drug Delivery Systems Electron Microscopy Enzyme Activation Enzymes Epithelial Epithelial Cells Failure Figs - dietary Gap Junctions Growth Growth Factor Health Heart Human Hydrogen Peroxide Hypoxia Individual Insulin-Like Growth Factor I Ischemia Ischemic Stroke Knock-out Knockout Mice Lens Fiber Longevity Macular degeneration Maintenance Mass Spectrum Analysis Measurement Mitochondria Modeling Oxidases Oxidative Stress Oxygen Phosphorylation Phosphorylation Site Property Protein Isoforms Protein Kinase Protein Kinase C Proteins Reporting Research Retina Role Signal Transduction Site Stress Stroke System Tissues Work citrate carrier electric impedance fiber cell lens lens cortex lens intrinsic protein MP 70 lens protein novel prevent protein kinase C epsilon protein kinase C gamma public health relevance response

项目摘要

All tissues must accommodate stress and growth signals in order to survive. The lens must also function under natural hypoxia, a condition which is so detrimental in heart and brain that one result is ischemic stroke. Ischemic damage is propagated through the gap junction protein, Cx43, and it is protein kinase C (PKC) epsilon which provides protection from damage in heart (1). In contrast, we have found that the lens contains two stress switch PKC isoforms, PKC gamma (PKCγ) and PKC epsilon (PKCε), which both play a stress protection role in the lens (2). During oxidative stress the PKCγ may function to inhibit gap junction proteins, Cx43, Cx50 and Cx46. In contrast, the PKCε is activated by hypoxia and is always found in the mitochondria. The long-term objective of our research is to determine how PKCs protect the lens from cataract formation. PKCγ and PKCε are both part of a large group of stress-switch C1B-containing proteins. C1B domains are zinc-finger/cysteine-rich domains which can be activated by cellular regulatory signals. The overall hypothesis of this proposal is: The lens, which thrives under natural hypoxia, contains two stressswitch PKC isoforms, PKCγ and PKCε, which provide protection during differentiation, hypoxia, and oxidative stress. We have previously reported that oxidative stress signals, such as hydrogen peroxide or the growth factor, IGF-1, activate lens PKCγ and cause the inhibition of the gap junction proteins, Cx43, Cx50, and Cx46, and protection of the lens from oxidative stress and cataracts. In contrast, we find that PKCε is not activated under these same conditions but is activated only by hypoxia (2). The hypoxia-driven activation of PKCε results in translocation to the lens mitochondria and activation of lens mitochondrial cytochrome C oxidase IV (cytIV) and in increased cytIV activity (3). We hypothesize that hypoxia induced activation of cytIV may help to prevent mitochondrial-driven apoptosis which could normally occur under hypoxic conditions in the differentiating lens. Thus, these two PKC isoforms protect the lens through phosphorylation of their respective targets, gap junction proteins (PKCγ targets) and mitochondrial cytIV (PKCε target).

所有组织都必须适应压力和生长信号才能生存。透镜还必须在自然缺氧的情况下发挥作用，这种情况对心脏和大脑非常有害，导致缺血性中风。缺血性损伤通过差距连接蛋白Cx43传播，并且是蛋白激酶C（PKC）激酶，其提供保护以免受心脏损伤（1）。相反，我们发现透镜含有两种应力开关PKC亚型，PKC γ（PKCγ）和PKC β（PKCε），它们都在透镜中发挥应力保护作用（2）。在氧化应激过程中，PKCγ可能起抑制间隙连接蛋白Cx43、Cx 50和Cx46的作用。相比之下，PKCε被缺氧激活，并且总是在线粒体中发现。我们研究的长期目标是确定PKC如何保护透镜免受白内障形成。PKCγ和PKCε都是一大组含C1 B的应激开关蛋白的一部分。C1 B结构域是富含锌指/半胱氨酸的结构域，其可以被细胞调节信号激活。该建议的总体假设是：在自然缺氧条件下生长的透镜含有两种应力开关PKC亚型，PKCγ和PKCε，它们在分化、缺氧和氧化应激期间提供保护。我们以前曾报道过氧化应激信号，如过氧化氢或生长因子IGF-1，激活透镜PKCγ，抑制差距连接蛋白Cx43、Cx 50和Cx46，保护透镜免受氧化应激和白内障的影响。相比之下，我们发现PKCε在这些相同条件下不被激活，而仅被缺氧激活（2）。缺氧驱动的PKCε激活导致转运至透镜线粒体，激活透镜线粒体细胞色素C氧化酶IV（cytIV），并增加cytIV活性（3）。我们推测缺氧诱导的cytIV的激活可能有助于防止分化中的透镜在缺氧条件下正常发生的晶状体驱动的细胞凋亡。因此，这两种PKC亚型通过其各自靶点，间隙连接蛋白（PKCγ靶点）和线粒体cytIV（PKCε靶点）的磷酸化来保护透镜。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NMR structure/function relationships of peptides corresponding to the C1B1 Region of PKC gamma.

PKC gamma 的 C1B1 区域对应的肽的 NMR 结构/功能关系。

DOI：
10.2174/092986610789909485
发表时间：
2010
期刊：
Protein and peptide letters
影响因子：
1.6
作者：
Lauer,Jason;Banerjee,Debarshi;Shanks,Denton;Dai,Huaien;Gong,Yu-Xi;Prakash,Om;Takemoto,Dolores
通讯作者：
Takemoto,Dolores

PKC-gamma phosphorylation of connexin 46 in the lens cortex.

DOI：
发表时间：
2001-10
期刊：
Molecular vision
影响因子：
2.2
作者：
S. Saleh;L. Takemoto;D. Zoukhri;D. Takemoto
通讯作者：
S. Saleh;L. Takemoto;D. Zoukhri;D. Takemoto

Human serum albumin nanoparticles for efficient delivery of Cu, Zn superoxide dismutase gene

DOI：
发表时间：
2007-05
期刊：
Molecular Vision
影响因子：
2.2
作者：
Yun Mo;Micheal E. Barnett;D. Takemoto;H. Davidson;U. Kompella
通讯作者：
Yun Mo;Micheal E. Barnett;D. Takemoto;H. Davidson;U. Kompella

The interaction and phosphorylation of tropomodulin by protein kinase Calpha in N/N 1003A lens epithelial cells.

N/N 1003A 晶状体上皮细胞中蛋白激酶 Cα 与原调节蛋白的相互作用和磷酸化。

DOI：
发表时间：
2002
期刊：
Molecular vision [electronic resource].
影响因子：
0
作者：
Wagner,LynnM;Fowler,VeliaM;Takemoto,DoloresJ
通讯作者：
Takemoto,DoloresJ

Expression of superoxide dismutase in whole lens prevents cataract formation.

DOI：
发表时间：
2005-10
期刊：
Molecular vision
影响因子：
2.2
作者：
Dingbo Lin;Micheal E. Barnett;L. Grauer;J. Robben;Annie Jewell;L. Takemoto;D. Takemoto
通讯作者：
Dingbo Lin;Micheal E. Barnett;L. Grauer;J. Robben;Annie Jewell;L. Takemoto;D. Takemoto