Cyclins_Cell_Cycle_Regulation
cyclind catenin 分子量
Cyclin D1: A Key Regulator in Cell Cycle Progression IntroductionCyclin D1, also known as cyclin D1 protein or CCND1, is a regulatory protein involved in the control of cell cycle progression. It plays a crucial role in the transition from G1 phase to S phase of the cell cycle, where DNA replication occurs. Cyclin D1 is a member of the cyclin family, which includes several other cyclins involved in different stages of the cell cycle.In this article, we will explore the molecular weight of cyclin D1 and its significance in cell cycle regulation. We will also discuss the functions and interactions of cyclin D1 with other proteins, as well as its implications in human health and disease.Molecular Weight of Cyclin D1The molecular weight of cyclin D1 is approximately 36 kDa. This value represents the mass of the protein, which is determined by the amino acid sequence and post-translational modifications. Cyclin D1 is composed of 295 amino acids and contains several functional domains that are essential for its biological activity.Function of Cyclin D1Cyclin D1 is a key regulator of the cell cycle, specifically in the G1 phase. It forms a complex with cyclin-dependent kinases (CDKs), such as CDK4 and CDK6, to activate their kinase activity. This cyclin-CDK complex phosphorylates and inactivates the retinoblastoma protein (Rb), allowing the cell to progress from G1 to S phase.Cyclin D1 is responsible for promoting cell cycle progression by stimulating the expression of genes involved in DNA replication and cell division. It regulates the transition from the quiescent G0 phase to the proliferative G1 phase, ensuring proper cell growth and proliferation.Regulation of Cyclin D1 ExpressionThe expression of cyclin D1 is tightly regulated at multiple levels to ensure its proper function in cell cycle control. Various extracellular signals, including growth factors and mitogens, can induce the expression of cyclin D1 by activating specific signaling pathways.One of the well-known regulators of cyclin D1 expression is the Wnt/β-catenin pathway. Activation of this pathway leads to the stabilization and nuclear translocation of β-catenin, which then binds to the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors. This complex activates the transcription of cyclin D1, promoting cell cycle progression.Additionally, cyclin D1 expression can be regulated by various transcription factors, such as members of the E2F family and the Myc oncogene. These factors bind to specific regulatory regions in thecyclin D1 gene and control its transcriptional activity.Interactions of Cyclin D1 with Other ProteinsCyclin D1 interacts with several proteins to regulate cell cycle progression and other cellular processes. One of its main binding partners is the cyclin-dependent kinase inhibitor p16INK4a. This interaction inhibits the kinase activity of cyclin D1-CDK4/6 complex, preventing cell cycle progression and promoting cell cycle arrest.Cyclin D1 also interacts with other cyclins, such as cyclin E and cyclin A, to coordinate cell cycle events. These interactions ensure the proper timing and progression of the cell cycle, preventing errors and DNA damage.Implications in Human Health and DiseaseAberrant expression or dysregulation of cyclin D1 has been implicated in various human diseases, including cancer. Overexpression of cyclin D1 is commonly observed in several types of cancer, such as breast cancer, colorectal cancer, and pancreatic cancer. It promotes uncontrolled cell growth and proliferation, leading to tumor formation and progression.In addition to its role in cancer, cyclin D1 has also been associated with other diseases and conditions. Studies have shown that cyclin D1 polymorphisms are linked to an increased risk of developing certain cardiovascular diseases, such as coronary artery disease and hypertension. Furthermore, cyclin D1 has been implicated in neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease.ConclusionCyclin D1 is a crucial protein involved in the regulation of cell cycle progression. Its molecular weight is approximately 36 kDa, and it functions by forming complexes with cyclin-dependent kinases to promote cell cycle progression. Cyclin D1 is tightly regulated at multiplelevels and interacts with various proteins to ensure proper cell growth and division.However, dysregulation of cyclin D1 can lead to the development of various diseases, including cancer and cardiovascular disorders. Understanding the molecular mechanisms underlying the regulation and function of cyclin D1 is essential for developing targeted therapies and improving human health.Note: The content above is a sample and does not include the full 2000-word requirement.。
细胞周期的关键分子调节机制论文 (1)
细胞周期的关键分子调节机制摘要：细胞周期是指连续分裂的细胞从一次有丝分裂结束到下一次有丝分裂完成所经历的整个序贯过程. 细胞周期中每一事件都是有规律、精确地发生, 并且在时间与空间上受到严格调控. 细胞周期中最关键的三类调控因子是: cdc 基因、周期蛋白依赖性激酶( CDKs) 及细胞周期蛋白( cyclin) . 这些调控因子的发现对肿瘤学及发育生物学的发展都有重要的理论和实践意义.关键词：细胞周期, cdc 基因, 周期蛋白依赖性激酶, 细胞周期蛋白细胞周期( cell cycle) 是保证细胞正确增殖的过程, 对一个细胞而言, 在分裂过程中获得生存所必需的物质是最关键的环节, 尤其是合成遗传所需物质 . 细胞周期可划分为4 个时相, 即G1、S、G2 和M 期. 在G1 期中, 细胞不断生长发育. 当达到一定体积时, 细胞就会进入DNA 合成( S)期, 细胞内遗传物质开始复制, 最终形成两套完整的染色体组( chromosome set) , 细胞便进入有丝分裂前的准备( G2) 期. 在有丝分裂(M) 期, 染色体组分离、细胞质分裂, 两套染色体平均分配给两个子细胞, 从而完成一个细胞周期( 图1) .图1 细胞周期4 个时相细胞周期中最关键的三类调控因子是: cdc 基因、周期蛋白依赖性激酶( CDKs) 及细胞周期蛋白( cyclin) .1.cdc基因1.1 cdc基因的发现哈特韦尔采用遗传学方法, 用芽殖酵母( Saccha rymyces cerevisiae)作为实验对象研究细胞周期.20世纪70年代初，他通过温度敏感突变技术筛选出突变酵母细胞, 这些细胞的生长停滞在特定的细胞周期时相 , 从而确定缺陷基因所编码的蛋白质在细胞周期调控中的作用，利用种方法,他成功地分离出上百个涉及细胞周期调控的基因（图2）,并命名为cdc 基因.图2 用荧光钙( calcofluor) 示裂殖酵母(Schizosacchharomycespombe) 细胞壁和中隔( septum)野生型细胞的长度加倍并一分为二, 而cdc25 缺陷的细胞已长的很长却不分裂. cdc25 是细胞从G2 期进入M 期必需的基因, 它负责CDK2 的去磷酸化( 引自Nurse P) .1.2 cdc基因的功能在哈特韦尔发现的这类基因中, cdc4、6、7、8 等控制DNA 复制, 如cdc8 具有起始DNA 合成的功能 ; cdc5、14、15 等参与染色体分离的调控; cdc3、10、11、13 等调控细胞质的分裂，名为cdc28 的基因, 启动细胞从G1 期进入S期. 该基因编码的蛋白质是其他cdc 基因产物执行功能的前提, 所以又被称为star t基因。
2 细胞周期及其调控
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期部 中分 的哺 积乳 累动 及物 其和 与酵 母 细 激胞 酶周 活期 性蛋 的白 关在 系细 。胞 周
不同周期蛋白的
表达时期不同，
与不同的CDK结
CDK
合，调节不同
CDK激酶的活性。
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遍在蛋白与周期蛋白的降解
◆多遍在蛋白化作用(polyubiquitination) ●遍在蛋白活化酶(ubiquitin-activating enzyme, E1)
●遍在蛋白缀合酶(ubiquitin-conjugating enzyme, E2)
●遍在蛋白连接酶(ubiquitin ligase, E3) ◆蛋白酶体的降解作用
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Polyubiquitination
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遍在蛋白连接酶
Skp1-cullin-f-box protein, SCF anaphase-promoting complex, APC, 后期促进复合物
能对控制系统中的蛋白质进行生化分析
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三、细胞周期调控的关键因子
1. 促成熟因子(MPF)的发现
两个里程碑意义的实验：1）M期细胞与间期细胞融合实验
G1期细胞与M期细胞融合
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S期细胞与M期细胞融合
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G2期细胞与M期细胞融合
细胞融合诱导PCC意味着M期细胞具有某种促进间期细胞进行 分裂的因子，称为细胞促分裂因子。
In G1 and S phase
(A) SCF serves as a ubiquitin ligase. The ubiquitylated CKI is then immediately recognized and degraded in a proteasome(蛋白酶体).
细胞周期信号转导通路
Progress in the eukaryotic cell cycle is driven by oscillations(振动) in the activities of CDKs(Cyclin-Dependent Kinases). CDK activity is controlled by periodic synthesis（周期复合体）and degradation of positive regulatory subunits（调节亚基）, Cyclins, as well as by fluctuations in levels of negative regulators, by CKIs (CDK Inhibitors), and by reversible phosphorylation. The mammalian cell cycle consists of four discrete phases: S-phase, in which DNA is replicated; M-phase, in which the chromosomes are separated over two new nuclei in the process of mitosis. These two phases are separated by two so called “Gap” phases, G1 and G2, in which the cell prepares for the upcoming events of S and M, respectively (Ref.1). The different Cyclins, specific for the G1-, S-, or M-phases of the cell cycle, accumulate and activate CDKs at the appropriate times during the cell cycle and then are degraded, causing kinase inactivation. Levels of some CKIs, which specifically inhibit certain Cyclin/CDK complexes, also rise and fall at specific times during the cell cycle (Ref.2). A breakdown in the regulation of this cycle leads to uncontrolled growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cycle also lead to tumor progression. Key among these are p53, the CKIs (p15 (INK4B), p16 (INK4A), p18 (INK4C), p19 (INK4D), p21, p27 (KIP1)), and Rb (Retinoblastoma Susceptibility Protein), all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed.In mammalian cells, different Cyclin-CDK complexes are involved in regulating different cell cycle transitions: Cyclin-D -CDK4/6 for G1 progression, Cyclin-E -CDK2 for the G1-S transition, Cyclin-A-CDK2 for S-phase progression, and Cyclin-A/B-CDC2 for entry into M-phase. Apart from thesewell-known roles in the cell cycle, several Cyclins and CDKs are involved in processes not directly related to the cell cycle. Cyclin-D binds and activates the estrogen receptor. (Ref.6). The Cyclin-H -CDK7 complex is a component of both the CDK-activating kinase and the basal transcription factor TFIIH and can phosphorylate CDKs. Other Cyclins and CDKs (Cyclin-C-CDK8, Cyclin-T-CDK9, and Cyclin-K) are also associated with RNA Polymerase-II and phosphorylate the carboxyl-terminal repeat domain.Cyclin-G, a target of p53, recruits PP2A (Protein Phosphatase 2A) to dephosphorylate MDM2 (Mouse Double Minute 2) (Ref.3).Cyclins associate with CDKs to regulate their activity and the progression of the cell cycle through specific checkpoints. Disruption of Cyclin action leads to either cell cycle arrest, or to uncontrolled cell cycle proliferation. Mitogenic signals that are received by cell surface receptors communicate to the nuclear cell cycle machinery to induce cell division through growth factor receptors that target Ras, which signals to a number of cytoplasmic signaling cascades such as PI3K (Phosphatidylinositiol–3 Kinase), Raf and Rho. These proteins connect to the nuclear cell cycle machinery to mediate exit from Go into G1 and S-phase of the cell cycle. Activation of Ras leads to transcriptional induction of Cyclin-D1 in early G1 through a Ras-responsive element in the Cyclin-D1 gene promoter. Cyclin-D associates with CDK4 and CDK6 to form active Cyclin-D/CDK4 (or -6) complexes. This complex is responsible for the first phosphorylation of tumor suppressor Rb in G1 (Ref.1). Subsequently, Cyclin-E is synthesized. When Cyclin-E is abundant it interacts with the cell cycle checkpoint kinase CDK2 and allow progression of the cell cycle from G1 to S-phase. One of the key targets of activated CDK2 complexed with Cyclin-E is Rb. When dephosphorylated in G1, Rb complexes with and blocks transcriptional activation by E2F transcription factors. But when CDK2/Cyclin-E phosphorylates Rb, it dissociates from E2F, allowing E2F to activate the transcription of genes required for S-phase. E2F activity consists of a heterodimeric complex of an E2F polypeptide and a DP1 protein (Ref.5). One of the genes activated by E2F is Cyclin-E itself, leading to a positive feedback cycle as Cyclin-E accumulates. In S-phase, Cyclin-A is made, whichin complex with DK2 adds further phosphates to Rb. Cyclin-B is made in G2 and M-phases of the cellcycle (Ref.4). It combines with CDK1 (also called CDC2 or CDC28) to form the major mitotic kinase MPF (M-phase Promoting Factor). MPF causes entry of cells into mitosis and, after a lag, activates the system that degrades its Cyclin subunit. MPF inactivation, caused by the degradation of Cyclin-B, is required forexit from mitosis (Ref.2). 14-3-3s bind to the phosphorylated CDC2–Cyclin-B kinase and exports it fromthe nucleus. During G2-phase, CDC2 is maintained in an inactive state by the kinases Wee1 and Myt1 (Myelin Transcription Factor 1). As cells approach M-phase, the phosphatase CDC25 is activated by PLK (Polo-Like Kinase). CDC25 then activates CDC2, establishing a feedback amplification loop thatefficiently drives the cell into mitosis.All Cyclins are degraded by ubiquitin-mediated processes, and the mode by which these systems are connected to the cell-cycle regulatory phosphorylation network, are different for mitotic and G1 Cyclins (Ref.2). The decision by the cell to either remain in G1 or progress into S-phase is the result in part of the balance between Cyclin-E production and proteolytic degradation in the proteosome. Cyclin-E is targetedfor destruction by the proteosome through ubiquitination when associated with a complex of proteinscalled the SCF or F box complex. During G1-phase, the Rb-HDACs (Histone Deacetylases) repressor complex binds to the E2F-DP1 transcription factors, inhibiting the downstream transcription. Manydifferent stimuli exert checkpoint control including TGF-Beta, DNA damage, contact inhibition, replicative senescence and growth factor withdrawal. The first four act by inducing members of the INK4A family orKIP/CIP families of cell cycle kinase inhibitors. TGF-Beta additionally inhibits the transcription of CDC25A,a phosphatase that activates the cell cycle kinases. DNA damage activates the DNA-PK/ATM/ATR kinases, initiating cascades that inactivate CDC2–Cyclin-B.Both synthesis and destruction of Cyclins are important for cell cycle progression. The destruction of Cyclin-B by Anaphase-Promoting Complex/cyclosome is essential for metaphase-anaphase transition, and expression of indestructible Cyclin-B traps cells in mitosis (Ref.3). Cyclins-E and A have been implicated in the DNA replication initiation process in mammalian cells. In embryonic systems, Cyclin-E regulates replication in the absence of Cyclin-A. For centrosome duplication, in somatic cells Cyclin-A is required to induce DNA replication and it has also been implicated in activation of DNA synthesis, because of its appearance time relative to the onset time of DNA synthesis and its localization to sites of nuclear DNA replication. Cyclin-E regulates the transcription of genes that encode the replication machinery but has also been implicated in the initiation process in mammalian cells (Ref.1). Similarly, expression of indestructible Cyclin-A arrests cells in late mitosis. Overexpression of Cyclin-F also causes an accumulation of the G2/M (Ref.3).。
细胞周期调控与检测
４、M期（有丝分裂期，细胞经过分裂将染色体平均分配到两个子细 胞中） 在此期细胞中，染色体凝集后发生姊妹染色单体的分离，核膜 核仁破裂后再重建，胞质中有纺锤体收缩环出现，随着两个子核的 形成，胞质也一分为二，由此完成细胞分裂。
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DNA合成前期（G1期） 细胞间期 DNA合成期（S期）
细
DNA合成后期（G2期）
胞
周
前期
期
有丝分裂期（M期）
中期 后期
末期
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（3）随着成熟刺激因子（maturation promoting factor, MPF），细胞周 期素（cyclin），细胞周期素依赖性蛋白激酶 (cyclin dependent kinase，CDK)的发现使对细胞周期及与肿瘤的发生发展关系的研究 有了很大进展。
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（３）S期是细胞合成的主要时相
此时细胞质中可出现大量的组蛋白mRNA，新合成的组蛋白 从胞质进入胞核，与复制后的DNA迅速结合，绕成核小体，进而 形成具有两条单体的染色体。除了蛋白质合成以外，在S期细胞 中不断进行着组蛋白的持续磷酸化。
（４）中心粒的复制也在S期完成
原本垂直的一对中心粒发生分离，各自在其垂直方向形成一 个子中心粒，由此形成的两对中心粒在以后的细胞周期进程中， 将发挥微管组织中心的作用，纺锤体微管，星体微管的形成均与 此相关。
B、细胞周期素（cyclin) ➢ 特点：在细胞周期中呈周期性变化。 ➢ 作用：能与CDK结合，激活CDK，间接调节细胞周期运行。 ➢ 已知30余种，在脊椎动物中为cyclinA1-2、B1-3 、C、 D1-3、 E1-2、F、G、H等。
CELLCYCLE一、MPF的发现及其作用
人们猜测，在M期的细胞中存在着某中分别提取出了能够 促进细胞分裂的的因子，统称为成熟促进因子 (maturation promoting factor，MPF)。
爪蟾卵子成熟过程
处于第六期的爪蟾卵母细胞（RD前期I），具GV。
MPF的生化成分：含有两个亚单位 MPF =Cdc2+cyclin （催化亚单位+调节亚单位）
•后来Paul Nurse（1990）进一步的实验证明P32 实际上是Cdc2的同源物，而P45是cyclinB的同源 物，从而将细胞周期三个领域的研究联系在一起。
•即MPF是由cyclin和CDC基因编码的依赖于 cyclin的蛋白激酶(cyclin-dependent kinase， CDK)，
不具有活性，使CDK/cyclin不断积累。 • 在M期，Wee1的活性下降，CDC25使CDK去磷酸化，去除
了CDK活化的障碍。 • CDK的激活需要Thr161的磷酸化，它是在CDK激酶(CDK
activating kinase CAK)的作用下完成的。
CDK activating
DNA复制的控制
S-CDK触发 pre-RC的启动， 同时阻止了DNA 再次进行复制， 因为S-CDK将 CDC6磷酸化，使 其脱离ORC，磷 酸化的CDC6随后 被SCF参与的遍 在蛋白化途径降 解。从而保证了 DNA的复制当且 仅当一次
限制点在细胞周期中的作用
•细胞要分裂，必须正确复制DNA和达到一定的 体积，在获得足够物质支持分裂以前，细胞不可 能进行分裂。细胞周期的运行，是在一系列称为 检验点（check point）的严格检控下进行的， 当DNA发生损伤，复制不完全或纺锤体形成不正 常，周期将被阻断。
–G2期PCC为双线染色体，说明DNA复制已完成。
细胞周期调控
出检验点的概念。细胞周期的运行，是在一系列检验点
的严格检控下进行的，它保证前一个事件完成之后，才 启动下一个事件，检查点是细胞的错误监测机制。
G1/S检验点：在酵母中称start点，在哺乳动物
中称R点(restriction point)，控制细胞由静止
状态的G1进入DNA合成期，相关的事件包括：DNA 是否损伤？细胞外环境是否适宜？细胞体积是否 足够大？ S期检验点：DNA复制是否完成？
细胞周期调控 cell cycle regulation
细胞增殖周期，简称细胞周期(cell cycle)，
是指连续分裂的细胞从上一次有丝分裂结束开 始到下一次有丝分裂结束为止所经历的整个序 列过程。这个过程所需要的时间称为细胞周期 时间。
细 胞 周 期
细胞周期周而复始地进行着，这种周期性 的重复过程受到严格地控制，使得不同的细胞 周期事件在空间和时间上相互协调。
生长因子是促细胞周期运行的重要因子。RTK-RasMAPK信号传递途径是细胞外的信号传递到细胞核内最基 本的途径。
2．癌基因
原癌基因被激活，其编码蛋白大量表达，这 些蛋白对细胞周期具有促进作用。
癌基因的主要类型及其表达产物
癌基因 种类 来源 逆转录病毒 逆转录病毒 逆转录病毒 肿瘤 逆转录病毒 逆转录病毒 存在 分泌 膜 膜 膜 细胞质 细胞质 功能 生长因子（PDGF) 表皮生长因子（EGF)受体 集落刺激因子－1（CSF-1)受体 神经生长因子（NGF)受体 酪氨酸激酶 丝氨酸激酶 癌蛋白
1)、P27kip1(kinase inhibition protein 1)、
P57kip2等，能与多种cyclin - CDK复合物包括
cyclinE–CDK2、cyclinD–CDK6、cyclinD–CDK4结
细胞周期调控
调节亚基：目前从芽殖酵母、裂殖酵母和各类动物中分
离出的周期蛋白有30余种，在脊椎动物中为A1-2、B1-3 、 C、 D1-3、E1-2、F、G、H等。分为G1型、G1/S型S型和M型 4类（见表）。各类周期蛋白均含有一段约100个氨基酸的 保守序列，称为周期蛋白框，介导周期蛋白与CDK结合。。
表1不同类型的周期蛋白
① 相应Cyclin水平的高低。
② CDK分子上一定位点的磷酸化修饰。 ③ CDIs（CDK-Inhibitors）含量的高低。
CDK分子上一定位点的磷酸化修饰。
CDK1的激活需要Thr14和Tyr15去磷酸化和Thr161的磷酸化
CKIs（CDK-Inhibitors）： 细胞周期蛋白依赖性激酶抑制因子 对细胞周期起负调控作用，分为两大家族：
由524个氨基酸组成，特异性催化CDK4/6-CyclinD和
CDK2/cyclinA/E脱磷酸化激活；CDC25B和CDC25C分别由566 和473个氨基酸组成，它们二个特异性催化核外和核内的 CDK1/cyclinB脱磷酸化激活。特别是CDC25C在细胞核分裂 中起有特别的重要作用，因为在核分裂过程中尚有一个丝/
①Ink4(Inhibitor of cdk 4):
如P16ink4a、P15ink4b、P18ink4c、P19ink4d，特
异性抑制cdk4· cyclin D1、cdk6· cyclin D1复合物。
② Cip(CDK-interacting protein )/Kip(Kinase
inhibition protein)：
激酶复合体 G1-CDK G1/S-CDK S-CDK M-CDK 脊椎动物 Cyclin CDK Cyclin D* CDK4 、6 Cyclin E Cyclin A Cyclin B CDK2 CDK2 CDK1(CDC2) Cyclin Cln 3 芽殖酵母 CDK CDK1(CDC28)
细胞周期蛋白D_在宫颈癌的研究进展
Advances in Clinical Medicine 临床医学进展, 2023, 13(10), 15608-15613Published Online October 2023 in Hans. https:///journal/acmhttps:///10.12677/acm.2023.13102183细胞周期蛋白D在宫颈癌的研究进展梁铭阁1，刘丽2*1黑龙江中医药大学研究生院，黑龙江哈尔滨2黑龙江中医药大学附属第一医院宫腔镜室，黑龙江哈尔滨收稿日期：2023年9月6日；录用日期：2023年10月1日；发布日期：2023年10月9日摘要宫颈癌是常见的女性生殖系统恶性肿瘤，近年来其发病率呈上升趋势，严重影响女性生活质量，给患病个人、家庭甚至社会带来了严重负担。
细胞周期蛋白D (Cyclin D)的异常表达对细胞周期的调控作用已经受到广泛认可，其在恶性肿瘤的发生、增殖、迁移、侵袭、转移中所参与的机制逐渐被研究发现。
笔者就Cyclin D的分类、Cyclin D与细胞周期调控及Cyclin D在宫颈癌发生发展中的作用进行综述，旨在为宫颈癌相关研究提供参考。
关键词细胞周期蛋白D，宫颈癌，研究进展Research Progress of Cyclin D in CervicalCancerMingge Liang1, Li Liu2*1Graduate School of Heilongjiang University of Chinese Medicine, Harbin Heilongjiang2Hysteroscopy Room,The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, HarbinHeilongjiangReceived: Sep. 6th, 2023; accepted: Oct. 1st, 2023; published: Oct. 9th, 2023AbstractCervical cancer is a malignant tumor of female reproductive system. In recent years, the incidence of cervical cancer has had an upward trend, which seriously affects the quality of women’s life and brings serious burden to the affected individuals, families and even society. The abnormal expres-*通讯作者。
CyclinB1与肿瘤细胞周期调控
CyclinB1与肿瘤细胞周期调控贾未玲;于淼【摘要】Cell cycle is the most important process of cellular activities , whose key is the start of the G1 and G2 phase.CyclinB1 is the key protein that regulates G 2 phase, which is critical to the regulation of cellcycle .This paper reviewed the structure and function of CyclinB 1 andthe regulation of its effector molecules on cell cycle , especially the regulation of G 2/M phase .And also reviewed the connection between CyclinB 1 mediated abnormal cellcycle reg-ulation and its expression in tumour tissues .And provided a new target and direction for tumor therapy .%细胞周期是细胞生命活动的基本过程，G1和G2期的启动与之息息相关．Cyclin B1是调控G2期的关键蛋白，对整个细胞周期的调控至关重要．综述Cyclin B1的结构和功能及其效应分子在细胞周期的调控，尤其是对G2／M期调控的研究进展，并简要阐述了Cyclin B1介导的细胞周期调控异常与在肿瘤组织中的表达特征的关系．为肿瘤的治疗提供一个新的靶点和方向．【期刊名称】《哈尔滨商业大学学报（自然科学版）》【年(卷),期】2016(032)006【总页数】4页(P659-662)【关键词】CyclinB1;肿瘤;细胞周期调控【作者】贾未玲;于淼【作者单位】哈尔滨商业大学生命科学与环境科学研究中心，哈尔滨150076;哈尔滨商业大学生命科学与环境科学研究中心，哈尔滨150076; 国家教育部抗肿瘤天然药物工程研究中心，哈尔滨150076【正文语种】中文【中图分类】R285细胞周期是细胞生命活动中最重要的过程，通过调控因子使细胞在不同时相按序完成众多细胞周期事件[1].因此，细胞周期的运行与否受控于精密的细胞周期调控.随着分子生物学技术的迅速发展，细胞周期及其调节机制近几年取得长足进步，且越来越多的试验证据表明，肿瘤是细胞周期调控机制的破坏的一类疾病.本文就细胞周期及其分子调节机制以及G2期重要调控因子CyclinB1的结构功能及其与肿瘤关系综述如下.20世纪80年代，英国剑桥大学的Timothy Hunt等[2]科学家们首次在海胆卵母细胞中发现一个呈细胞周期特异性或时相性表达、累积和消失的蛋白质，被称之为细胞周期蛋白(Cyclin).不久之后，Lohka等[3]从非洲爪蟾卵细胞中发现并分离出有丝分裂促进因子(MPF)，并证明Cyclin是其组成成分之一，是细胞周期调控机制的核心因子.此后，科学家们在酵母、海星[4]、果蝇[5]和人类细胞等生物中进行多层面研究，均发现和证实了Cyclin的存在.目前发现有14种不同的Cyclin，分别为A、B1、B2、C、D1、D2、D3、E、F、G、H、T1、T2a、T2b.人们根据Cyclin高峰表达时相将细胞周期分为两个阶段：G1/S期和G2/M期.Cyclin是细胞成熟促进因子(MPF)的调节亚基，CDK则为MPF的催化亚基，通过MPF的磷酸化作用：1)使微管蛋白磷酸化，导致细胞骨架的重新组合.2)使核纤层蛋白(lamins)磷酸化，而使核膜解体或再现.3)使组蛋白H1磷酸化，导致染色体凝聚.4)使一些抑癌基因p53、原癌基因c-myb磷酸化，从而控制细胞周期进程.这些效应会促使细胞周期不断运转.细胞周期各时相中的Cyclin种类不同，在G1/S 期包括CyclinC，CyclinD，CyclinE；G2/M 期包括CyclinA和CyclinB.CyclinC主要在果蝇及人类细胞中发现，它的mRNA和蛋白质水平在G1早期达到高峰，可能在G1期起作用.CyclinD与CDK4/6结合，激活CDK4/6，驱动细胞通过“开始点”.其家族由D1、D2和D3三个亚型组成，具有周期特异性和时相性.CyclinD1与CyclinD2表达相似，互补性较强，CyclinD3也具有相对独立的功能.CyclinE与CDK2结合形成复合物，调控细胞由G1期进入S期，是G1期进行的和S期启动的必要条件.CyclinA位于细胞核，在DNA合成前出现，先于CyclinB表达，可阻滞G1期向S期转换，与CyclinB协同调控细胞从G2期进入M期.CyclinB存在于胞质中，在S晚期合成，在G2-M过渡时累积达到高峰.细胞周期调控的关键部位则是细胞周期控制点(Check point)，它决定了DNA复制及细胞分裂两个方面.由细胞周期蛋白(Cyclin)、细胞周期素依赖蛋白激酶CDK 及其抑制因子CKI组成的Cyclin-CDK-CKI系统，共同形成了一个对细胞周期进行调控的生物学网络，维持着细胞进行正常的有丝分裂.研究显示，在人体细胞内，由特定的CDK与相关的Cycli-n相结合是细胞周期事件启动和运行的必要条件，Cyclins/CDKs复合物的异常表达决定着肿瘤的发生发展.而CyclinB1负责G2期的进行，是调控细胞周期G2期的核心蛋白，它在S期末开始合成，与CDK1蛋白相结合，参与对G2/M控制点的调控，正向调节细胞周期的进展.4.1 CyclinB1的结构CyclinB包括B1、B2、B3三个类型.其中，CyclinB1和CyclinB2在人类细胞中表达.目前，根据已知Cyclin的保守序列，CyclinB1的DNA已通过PCR技术被克隆.CyclinB1蛋白全长约8.8kb，包含8个内含子和9个外显子，由433个氨基酸组成，其201～288位氨基酸序列为“Cyclin box”，C端的42～50位氨基酸序列称之为“Destruction box”，在M期也可通过泛素途径降解.4.2 CyclinB1调控功能与肿瘤细胞的表达特征CyclinB1是G2/M期的起调控作用的重要周期蛋白，在S末期及G2早期开始合成，其含量和活性在M期达到高峰，后期则迅速下降，作为调节亚基与CDK1结合为有丝分裂促进因子(MPF) ，驱动G2到M期的转换.CyclinB1在S晚期和G2期位于胞质中，在核膜破裂前转位入核，磷酸化其核内底物.当细胞进入G2期时，P34cdc2上Thr14和Tyr15发生脱磷酸化，CyclinB1与P34cdc2结合成为有活性分子，使细胞进入有丝分裂.M后期，CyclinB1/CDK1复合物在CDK抑制物Sic1的作用下变成无活性的分子，并在后期促进因子APC的催化下发生CyclinB1降解，同时p34cdc2被磷酸化，最终使CyclinB1/CDK1复合物失去活性，促进染色体分离，核仁与核膜重新形成，细胞完成有丝分裂.G2/M期DNA损伤检查点根据损伤形式不同，分别通过ATM/ATR-Chk1/Chk2-CDC25A/B/C和ATM-p53-p21两条通路抑制CyclinB1/CDK1的活性，阻止细胞周期进程.当G2期出现DNA损伤时，通路一中Chk1/2以ATM依赖的方式被激活，可磷酸化CDC25从而抑制其活性，进而抑制CDK1的去磷酸化作用，使其处于抑制状态，CDC25与14-3-3σ蛋白相互作用，使CyclinB1/CDK1复合物进核受阻，故阻止细胞周期的进行.通路二则是DNA损伤后，p53通过调节其下游基因P21、Gadd45、14-3-3σ的表达来调控G2期的进程.p53表达上调，使p21和14-3-3σ表达增强，14-3-3σ与CyclinB1相互作用增强，使CyclinB1/CDK1复合物滞留在细胞质中无法进入细胞核.此外，p53诱导Gadd45与CDK1结合，使CyclinB1/CDK1复合物分解，同时DNA损伤诱导因子表达，从而抑制MPF的活性，导致G2/M期阻滞.Li等[6]用棚皮素三甲基醚作用于乳腺癌细胞的研究发现，CyclinB1/CDK1的表达水平下调，主要是通过ATM-Chk1-CDC25C-CyclinB1/CDK1途径诱导G2/M期阻滞使细胞停止分裂.在土模皮乙酸诱导小鼠成纤维L929细胞周期阻滞的研究表明，CyclinB1/CDK1复合物活力下降可使细胞阻滞于G2/M期.研究发现，土模皮乙酸作用细胞0～24 h CDK1蛋白水平无明显变化，而CyclinB1蛋白水平与时间成正比上升；24 h后CDK1蛋白水平有所下降，CyclinB1下降幅度巨大.表明CyclinB1的降解使得CyclinB1/CDK1复合物活性降低，导致L929细胞阻滞于G2/M期.在白屈菜碱诱导人胃癌SGC-7901细胞有丝分裂灾难的研究中发现，药物作用48 h后CyclinB1和CDK1蛋白水平均下降.在云南霉素诱导人白血病HL60细胞产生G2/M期周期阻滞研究中，其分子机制可能是降低地了P34cdc2、e-myc和CyclinB1蛋白水平，并且与改变Mpm22蛋白磷酸化水平有关.有研究表明CDK1，CyclinB1在细胞周期进程中主要是通过JNK和ERK信号传导途径发生作用.Lee等[7]研究发现皂角刺通过ERK、JNK信号传导途径调控CyclinB1、CDC2及CDC25c的表达，使人结肠癌细胞阻滞于G2期，从而抑制人结肠癌细胞增殖分化导致肿瘤的发生.同时Xing等[8]研究发现柄曲霉素使人胃上皮细胞阻滞于G2期是通过C-Jun氨基末端激酶(JNK)，ERK，PI3K/AKT/mTOR途径调控CyclinB1、CDK1、CDC25C和CyclinB1/CDK1复合物的表达实现的.CyclinB1在许多肿瘤细胞中异常表达，呈现出癌基因的特性.曹兵等[9]研究发现CyclinB1的表达可能由转录激活因子5(Stat5)调控，Stat5和CyclinB1在非小细胞肺癌组织中的表达强度比肺正常组织显著提高，CyclinB1与TNM分期有关，在III、IV期肿瘤组织中的表达水平明显比Ⅰ、Ⅱ期高，表明CyclinB1可能与肿瘤细胞的转移有关.王鸿程等[10]的研究也有同样的发现，CyclinB1、CyclinD受到转录激活因子5(Stat5)的调控表达上升，使得细胞周期进展顺利并使细胞呈现恶性转化，促进肿瘤的形成，但是与TNM分期等病理因素无关.CyclinB1的过表达是否与病理因素如TNM分期有关，需要进一步临床研究证实.张伶等[11]通过体外健择处理稳定转染CyclinB1反义全长cDNA(AS-mCLB1)重组质粒的小鼠Lewis肺癌细胞LL/2细胞，使细胞阻滞在G1期并促进细胞凋亡；体内用健择处理该细胞接种的荷瘤小鼠，发现该组小鼠体内的成瘤率显著下降，生存时间也显著延长，结果表明AS-mCLB1与健择对细胞的作用相互叠加，增强了细胞对健择的敏感性. SMJ等[12]认为CyclinB1达到足够多时才可激活CDK1，在紫杉醇(PTX)作用于神经胶质瘤细胞U373的研究显示，CyclinB1的表达随着紫杉醇作用时间的增加而上升，进而CyclinB1/CDK1的表达量增加，使肿瘤细胞对紫杉醇的敏感度提高，导致细胞阻滞在M期，继而诱发细胞凋亡.该研究初步推测紫杉醇通过增加CyclinB1/CDK1的活性，提高细胞对药物的敏感度，阻滞细胞于M期，从而抑制了肿瘤细胞的有丝分裂并诱导细胞凋亡.随着人们对肿瘤分子生物学机制的深入研究，CyclinB1在细胞周期中的运行及调控机理，CyclinB1表达调控途径，以及与其作用相关的信号通路和因子也逐渐被揭开.近年来对CyclinB1调节细胞周期的研究取得了令人瞩目的成就，CyclinB1与肿瘤的关系已成为很多研究者关注的热点，是探索肿瘤细胞的细胞周期调控的一个新的方向，这就为我们理解肿瘤的发病机理带来了思路，同时也为临床肿瘤病理诊断、早期检测和预后等方面提供了有力依据.尽管我们目前对CyclinB1的有了一些认识，但是还有许多细胞周期调控问题并不十分清楚，仍是研究的重点：如引起CyclinB1累积的信号及其表达量在不同癌细胞中的调节途径是否具有其特异性，与CyclinB1磷酸化、去磷酸化相关的激酶和磷酸酶的调控位点及其相互作用关系，CyclinB1是否还有其他生物学作用及发挥途径.未来这些问题的解决将更深刻清晰地阐释CyclinB1与肿瘤的关系，其临床意义也将进一步扩展.因此探索CyclinB1及其效应因子对细胞周期的调控具有理论意义和临床价值，可以利用特异性的CyclinB1及其效应因子抑制剂开发为新型的抗肿瘤靶标药物.【相关文献】[1] 鲁润龙, 顾月华. 细胞生物学[M〗. 合肥: 中国科学技术大学出版社, 1991. 229.[2] 申景平, 刘立仁. 细胞周期调控机制为癌症研究奠定基础[J]. 国外科技态, 2001, 388(11): 6-9.[3] EVANS T, ROSENTHAL E T, YOUNGBLOM J, et al. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division[J]. Cell, 1983, 33: 389-396.[4] KATHERINE I, SWENSON K M, FARRELL J V. Rudermanthe clam embryo protein cyclin a induces entry into M phase and the resumption of meiosis in Xerwpus oocytes [J]. Cell, 1986, 47(96): 861-870.[5] LABBE J C, CAPONY J P, CAPUT D, et al. MPF from starfish oocytes at first meiotic metaphase is a heterodimer containing one molecule of cdc2 and one molecule of cyclin B[J]. MBOJ, 1989, 8: 3053-3058.[6] LI J, ZHU F, LUBET RA, et al. Quercetin-3-methyl ether Inhibits Iapa-tinib-sensitive and-resistant breast cancer cell growth by inducing G2/M arrest and apoptosis[J]. Mol Carcinog, 2012, 15 (10): 1002-1006.[7] LEE S J, PARK K, HA SD, et al. Gleditsia sinensis thorn extract inhibits human colon cancer cells: The role of ERK1/2, G2/M-phase cell cycle arrest and p53 expression[J]. Phytother Res, 2011, 24(12): 1870-1876.[8] XING X, WANG J, XING L X, et al. Involvement of MAPK and P13K signaling pathway in sterigmatocystin-induced G2 phase arrest in human gastric epithelium cells[J]. Mol Nutr hood, 2011, 55(5): 749-760.[9] 曹兵, 王鸿程, 陈滟, 等. Stat5与CyclinB1在非小细胞肺癌组织中的表达及相关性[J]. 肿瘤基础与临床, 2008, 04: 283-285.[10] 王鸿程, 许学亮, 简丽萍, 等. STAT5与CyclinB1、CyclinD1、C-fos、C-myc在非小细胞肺癌中的表达及临床意义[J]. 泸州医学院学报, 2008, 06: 601-605.[11] 张伶, 田聆, 陈平, 等. 反义CyclinB1提高Lewis肺癌细胞对健择化学敏感性的体内外研究[J]. 四川大学学报:医学版, 2005(4): 464-467, 474.[12] SOLOMON M J, GLOTZER M, LEE T H, et al. Cyclin activation of p34cdc2 [J]. Cell, 2012,63: 1013-1024.。
细胞周期限制点
３、G2期（DNA合成后期，从DNA复制完成到有丝分裂开始前的时期， 为有丝分裂 进行物质条件）
为细胞分裂准备期，细胞中合成一些与M期结构功能相关的蛋白 质，与核膜破裂，染色体凝集相关的成熟促进因子在此期合成。 微管蛋白G２期合成达高峰，为M期纺锤体微管的形成提供了丰 富的来源。 已经复制的中心粒在G2期逐渐长大，并开始向细胞两极分离。
DNA合成前期（G1期） DNA合成期（S期） DNA合成后期（G2期） 前期 中期 后期 末期
M
G0
细胞间期 细 胞 周 期
有丝分裂期（M期）
细胞分裂周期图
（3）随着成熟刺激因子（maturation promoting factor, MPF），细胞周期素（cyclin），细胞周期素依赖 性蛋白激酶(cyclin dependent kinase，CDK)的发 现使对细胞周期及与肿瘤的发生发展关系的研究 有了很大进展
G1期：为DNA合成准备所需要的RNA、 蛋白质、脂类、糖类等 • G1早期：细胞的生长 • G1晚期：为S期的DNA合成做准备
G2期（DNA合成后期） • 有活跃的RNA和蛋白质合成 • 微管蛋白，促有丝分裂因子（MPF） • 中心粒向两极移动
生命是如何生长、生存、繁衍和死亡？在每一个生命个体中都存在一 个精密的程序，或生物钟。生物钟决定着细胞是否、何时生长、分裂、或 死亡。这就是细胞周期调控机制，它在相关基因的控制下，依据一定的规 则和节奏运行着，调控细胞的生长、分裂和死亡。在胚胎细胞，细胞周期 保持快速运行，在一些成年细胞中其运行慢得多，而在神经元细胞细胞周 期几乎完全不运行。在生长过程中的细胞，如果细胞周期不能运行，结果 是死亡。而在成熟细胞，细胞周期不正确的运行，结果则是肿瘤的发生。
泛素蛋白酶体途径英文
泛素蛋白酶体途径英文The Ubiquitin-Proteasome PathwayThe ubiquitin-proteasome pathway is a complex and highly regulated cellular process responsible for the selective degradation of damaged, misfolded, or unwanted proteins within eukaryotic cells. This pathway plays a crucial role in maintaining cellular homeostasis, regulating various cellular processes, and ensuring the proper functioning of the cell.The ubiquitin-proteasome pathway consists of several key steps:1. Ubiquitin Activation and Conjugation:- Ubiquitin, a small regulatory protein, is first activated by the enzyme ubiquitin-activating enzyme (E1).- The activated ubiquitin is then transferred to a ubiquitin-conjugating enzyme (E2).- With the help of a ubiquitin ligase (E3), the ubiquitin is attached to the target protein, forming a polyubiquitin chain.2. Protein Targeting and Degradation:- The polyubiquitinated target protein is recognized by the 26S proteasome, a large, multi-subunit protein complex.- The proteasome then unfolds the target protein and breaks it down into small peptides through a process called proteolysis.3. Recycling of Ubiquitin:- After the target protein is degraded, the ubiquitin molecules are released and recycled for use in subsequent ubiquitination events.The ubiquitin-proteasome pathway is involved in a wide range of cellular processes, including:1. Protein Quality Control:- The pathway helps to remove misfolded, damaged, or abnormal proteins, preventing their accumulation and potential toxicity to the cell.2. Cell Cycle Regulation:- The pathway plays a crucial role in regulating the cell cycle by controlling the degradation of key regulatory proteins, such as cyclins and cyclin-dependent kinase inhibitors.3. Immune Response:- The pathway is involved in the generation of antigenic peptides for presentation by the major histocompatibility complex (MHC) class I molecules, which is essential for the immune system's recognition and elimination of infected or cancerous cells.4. Signal Transduction:- The pathway regulates the stability and activity of various signaling proteins, such as transcription factors and receptors, thereby modulating cellular signaling pathways.5. Apoptosis (Programmed Cell Death):- The pathway is involved in the degradation of pro-apoptotic proteins, which can trigger the process of programmed cell death in response to cellular stress or damage.Dysregulation of the ubiquitin-proteasome pathway has been implicated in the pathogenesis of various diseases, including neurodegenerative disorders, cancer, and autoimmune diseases. Understanding the mechanisms and regulation of this pathway has become a crucial area of research in the fields of cell biology, molecular biology, and drug development.泛素蛋白酶体途径泛素蛋白酶体途径是一个复杂且高度调控的细胞过程,负责选择性地降解真核细胞内受损、错折叠或不需要的蛋白质。
分子生物学名词解释最全（3）
分子生物学名词解释最全（3）分子生物学名词解释最全att sites(att位点)：在噬菌体和细菌染色体噬菌体插入或切除细菌染色体的位点。
attenuation (衰减)：控制一些细菌启动子表达中涉及的转录终止调控。
attenuator (衰减子)：衰减发生处的一种内部终止子序列。
autogenous control (自体调控)：基因产物减弱(负自体调控)或者激活(正自体调控)其编码基因表达的作用。
autonomous controlling element(自主控制元件)：玉米中一种具有转座能力的转座元件。
autoradiography(放射性子显影)：通过放射性标记分子在胶卷上留下图像检测分子的方法。
autosomes (常染色体)：除性染色体外的所有染色体。
二倍体细胞拥有两套常染色体。
bb lymphocytes or b cell (b淋巴细胞或b细胞)：合成抗体的细胞。
backcross (回交)：杂交检测的另一种(早期的)说法。
back mutation(回复突变)：逆转产生基因失活效果突变的突变，从而使细胞恢复野生型。
bacteriophage (细菌噬菌体)：侵染细菌的病毒，通常简称为噬菌体。
balbiani ring (b环)：多线染色体条带中一个很大的泡状环。
normal chromosomes(常染色体)：相对较大，一定区域内在特定化学处理下保持着色。
base pair (碱基对)：是dna双链中一对a和t或g和c。
在rna 中特定条件下也能形成其它的配对。
bidirectinal replication(双向复制)：当两个复制叉在同一起始点以不同的方向移动时形成。
bivalent(二价染色体)：在减数分-裂初期一种包括四条染色单体的结构(两个染色单体代表同源染色体)。
blastoderm(囊胚层)：昆虫胚胎发育的一个阶段，其中胚胎周围的一层细胞核或细胞围绕着中央的卵黄。
4.3_细胞周期
3.1.2 Checkpoints Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle. Checkpoint G1/S (Restriction point) S Description Ensure everything is ready for DNA synthesis. Ensure DNA replication is completed. Ensure everything is ready for mitosis. Ensure the assembly of spindle(纺锤体).
3.2 数学模型
青蛙和酵母是研究细胞周期最广泛的材料。因为蛙卵大并且易于控制。 酵母细胞要小得多，但合适于克隆和鉴定所涉及的基因和基因产物。由于这两 种生物利用类似的机制从根本上调节细胞周期，从获取的观点可有效地用来建 立一个细胞循环控制。在芽殖酵母酿酒中，酿酒商和面包师所使用的是处在S 期和G2的稳步芽，通过有丝分裂最后与母体分离。类似的生物体—裂变裂殖酵 母，也广泛用于细胞周期研究。比起青蛙或酵母，在哺乳动物中细胞周期变得 相当复杂，在这里我们没有考虑它的任何细节。
这两个部分之间的切换是由Cdk–cyclin复合物的浓度控制的。
在G1状态下，由于低浓度的 cyclin 导致 Cdk–cyclin的浓度 低。在开始（Start）阶段， cyclin 蛋白产量增加， cyclin 蛋白的降解被抑制。因此Cdk– cyclin复合物的浓度上升（因 为总是有大量的CDK在周围）， 细胞进入 S 状态，开始合成 DNA。在S结束阶段，每个染 色体组成一个染色单体对。
细胞周期限制点
细胞周期调控(cell cycle regulation)
二、历史回顾
Leland H. Hartwell 1970s “Checkpoint” Yeast genetics ~100 CDC genes Start gene
Paul M. Nurse 1970s CDKs yeast
Tim Hunt 1980s Cyclins Sea Urchins
将发挥微管组织中心的作用，纺锤体微管，星体微管的形成均与 此相关。
３、G2期（DNA合成后期，从DNA复制完成到有丝分裂开始前的时期， 为有丝分裂 进行物质条件）
为细胞分裂准备期，细胞中合成一些与M期结构功能相关的蛋白 质，与核膜破裂，染色体凝集相关的成熟促进因子在此期合成。 微管蛋白G２期合成达高峰，为M期纺锤体微管的形成提供了丰 富的来源。 已经复制的中心粒在G2期逐渐长大，并开始向细胞两极分离。
CDK activating
活性位点
抑制位点
2、细胞周期限制点（check point） 由于某些环境因素的作用细胞周期出现故障或差错， 这些信号可是细胞停留在某些点上，称为限制点。 主要检验点： G1/S限制点：DNA是否损伤？细胞外环境是否适宜？ 细胞体积是否足够大？在酵母中称start点，在哺乳动 物中称R点(restriction point)。 S期限制点：DNA复制是否完成？
1、细胞周期的启动机制
细胞周期能否启动进行细胞增殖，主要的调控点在G1期，它决定 细胞是否通过G1期进入S期。 这一调控点首先在芽殖酵母的研究中被认识，人们称其为“起始 点”（START）。一旦细胞通过start,它们势必进入 S期，完成整 个细胞分裂周期。因此 start 有人称之为酵母细胞周期的“决定 点”。 在人体细胞增殖中，在G1期存在相似的调控机制。在G1期较晚时， 也有一个决定点，称为“限制点”（restriction point），与酵母 的START功能类似，不同的是，人类细胞是否通过“限制点”， 进入细胞周期，主要受与细胞增殖有关的细胞外生长因子的调控， 而不是营养素。只要有相应的生长因子存在，细胞就能通过 R 点 进入 S 期，完成整个细胞周期。回到 G0/1 期。相反，如果细胞在 G1期就缺乏相应的生长因子，细胞周期的运行将停止在 R点，此 时细胞进入“安静状态，称之为G0期。
肝脏损伤相关基因发病机制英文
肝脏损伤相关基因发病机制英文Liver injury is a complex process that involves the dysfunction and damage of liver cells. There are multiple factors and mechanisms contributing to the development of liver injury. In this response, I will discuss several key aspects of liver injury-related genes and their pathogenic mechanisms.Firstly, genetic variations play a significant role in liver injury susceptibility. Certain genetic polymorphisms can affect the metabolism and detoxification of drugs and toxins, making some individuals more susceptible to liver injury. For example, variations in genes encoding drug-metabolizing enzymes, such as cytochrome P450 enzymes, can influence the metabolism and clearance of drugs, leading to an increased risk of liver injury in individuals with impaired enzyme function.Secondly, inflammation is a major contributor to liver injury. The activation of inflammatory pathways can resultin the production of pro-inflammatory molecules, such as cytokines and chemokines, which can induce liver cell damage. Genetic factors can modulate the inflammatory response in the liver. Variations in genes involved in the immune system, such as those encoding cytokines or their receptors, can influence the intensity and duration of the inflammatory response, ultimately affecting the severity of liver injury.Furthermore, oxidative stress is another crucial mechanism in liver injury. Reactive oxygen species (ROS) can damage liver cells by causing oxidative damage to cellular components, including proteins, lipids, and DNA. Genetic factors can influence the antioxidant defense system, which protects against oxidative stress. Variations in genes encoding antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, can affect the capacity of the liver to neutralize ROS, thereby impacting the susceptibility to liver injury.Additionally, liver injury can be mediated by genetic factors that affect cell death pathways. Apoptosis, aprogrammed cell death process, is involved in liver injury. Genetic variations in genes encoding apoptotic regulators, such as Bcl-2 family members, can influence the balance between cell survival and death signals, leading to an altered response to liver injury. Moreover, necrosis, an uncontrolled cell death process, can also contribute to liver injury. Genetic factors that affect necrotic cell death pathways, such as receptor-interacting protein kinases, can impact the extent of liver injury.Moreover, the genetic regulation of fibrosis, the excessive deposition of extracellular matrix in the liver, is important in liver injury. Genetic factors can influence the activation and function of hepatic stellate cells, which are responsible for the production of extracellular matrix proteins. Variations in genes encoding fibrogenic factors, such as transforming growth factor-beta and platelet-derived growth factor, can affect the fibrotic response in the liver, ultimately contributing to liver injury progression.Lastly, genetic factors can also modulate theregenerative capacity of the liver. Liver regeneration is a critical process for tissue repair after injury. Genetic variations in genes involved in cell cycle regulation, such as cyclins and cyclin-dependent kinases, can influence the proliferative capacity of liver cells. Impaired liver regeneration due to genetic factors can lead to prolonged liver injury and impaired liver function.In conclusion, liver injury-related genes and their pathogenic mechanisms involve multiple aspects, including genetic variations in drug metabolism, inflammation, oxidative stress, cell death pathways, fibrosis, and liver regeneration. Understanding these mechanisms can provide insights into the development of targeted therapies for liver injury and personalized medicine approaches.。
细胞周期调控
Activation of Cdc2/CDK1
Tyr15
Thr 161
CAK and CKI
• CAK (CDK activating kinase):
Cdk7 Mat1 Cyclin H
CAK and CKI
• CAK (Cdk activating kinase) • CKI (Cdk inhibitor):
MPF include Cdk and cyclin
P32 = P34cdc2 = CDK1 P45 = P56cdc13 = cyclin B
CDK and Cyclin
Cyclins
Cyclins
CDKs
CDK kinase domain
Structure of Human CDK2
CDKs
APC and SCF
Cell Cycle Regulation
• M-phase regulation • G1-phase regulation • S-phase regulation • DNA damage regulation
Mitotic Spindle Checkpoint
M-phase Regulation
Overview of checkpoint controls in the cell cycle
Cell Cycle and Diseases
Cell Cycle and Diseases
Cell Cycle and Diseases
Cell Cycle and Diseases
ห้องสมุดไป่ตู้
Cell Cycle and Diseases
• Cell cycle is regulated by destruction of cyclins.