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细胞周期抑制剂治疗肿瘤的进展
细胞周期是细胞生命活动的基本过程，它控制着细胞从静止期转向生长增殖期。细胞周期蛋白依赖激酶（Cdks）和细胞周期蛋白（Cyclins）是整个细胞周期调控机制中的核心分子。细胞周期调控异常与细胞癌变密切相关，90％以上的肿瘤，尤其是胶质瘤和软组织肉瘤中 Cdks 都有过度表达。进一步分析指出，Cdks 和 Cyclins 被作为治疗肿瘤的关键靶点，它们受抑制时能导致肿瘤细胞的死亡，抑制 Cdks 还能阻滞 Cyclins 转录。Ⅰ期临床研究提示，细胞周期素蛋白激酶抑制剂（CDKIs）有较高的安全性；Ⅱ期临床研究提示，CDKIs 联合细胞毒性化疗药物作用肿瘤细胞有更好的前景，且 CDKIs 的使用剂量和时间顺序决定着其最佳使用效果。本文阐述了 Cdks 和 Cyclins在肿瘤细胞周期中的表达，对 Flavopiridol、Indisulam、AZD5438、SNS-032（BMS-387032）、Bryostatin-1、PD 0332991等 CDKIs 在肿瘤靶向性治疗中的研究作一综述。
Abstract：
ABSTRACT:Cell cycle is the basic process of cell life activities.It controls the entry of stationary-phase cells into proliferative phase.Cyclin dependent kinases(Cdks)and cyclins play important roles in the regulatory mechanism of cell cycle.The dysregulation of cell cycle is closely related to the canceration.The Cdks is overexpressed in 90% of tumors,especially in glioma and soft tissue sarcoma.Cdks and cyclins are considered as the target of tumor therapy.Tumor cell death can be caused by the inhibition of both proteins.Furthermore,the transcription of cyclins can be inhibi-ted by Cdks.Phase Ⅰ clinical trial has shown that the cyclin-dependent kinase inhibitors(CDKIs) have higher security.Phase Ⅱ clinical trial has demonstrated that the combination CDKIs and cy-totoxic chemotherapy drugs has a better prospect and the dose and sequential order of usage of CDKIs are extremely important for their efficacy.This paper reviews the expression of Cdks and cyclins in tumor cell cycle and roles of flavopiridol,indisulam,AZD5438,SNS-032(BMS-387032), bryostatin-1,PD 0332991 and other CDKIs in target-guided tumor therapy.
FU Wen-feng
LIU Tian-reng
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南昌大学第一附属医院骨科,南昌,330006
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万方数据知识服务平台--国家科技支撑计划资助项目（编号：2006BAH03B01）(C)北京万方数据股份有限公司
万方数据电子出版社Selective degradation of ubiquitinated Sic1 by purified 26S proteasome yields active S phase cyclin-Cdk.
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):439-48.Selective degradation of ubiquitinated Sic1 by purified 26S proteasome yields active S phase cyclin-Cdk.1, , , .1Howard Hughes Medical Institute, Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.AbstractSelective degradation of single subunits of multimeric complexes by the ubiquitin pathway underlies multiple regulatory switches, including those involving cyclins and Cdk inhibitors. The machinery that segregates ubiquitinated proteins from unmodified partners prior to degradation remains undefined. We report that ubiquitinated Sic1 (Ub-Sic1) embedded within inactive S phase cyclin-Cdk (S-Cdk) complexes was rapidly degraded by purified 26S proteasomes, yielding active S-Cdk. Mutant proteasomes that failed to degrade Ub-Sic1 activated S-Cdk only partially in an ATP-dependent manner. Whereas Ub-Sic1 was degraded within approximately 2 min, spontaneous dissociation of Ub-Sic1 from S-Cdk was approximately 200-fold slower. We propose that the 26S proteasome has the intrinsic capability to extract, unfold, and degrade ubiquitinated proteins while releasing bound partners untouched. Activation of S-Cdk reported herein represents a complete reconstitution of the regulatory switch underlying the G1/S transition in budding yeast.PMID:
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External link. Please review our .Double-negative feedback between S-phase cyclin-CDK and CKI generates abruptness in the G1/S switch.
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2012 Dec 6;3:459. doi: 10.3389/fphys.. eCollection
2012.Double-negative feedback between S-phase cyclin-CDK and CKI generates abruptness in the G1/S switch.1, , , .1Institute of Technology, University of Tartu Tartu, Estonia.AbstractThe G1/S transition is a crucial decision point in the cell cycle. At G1/S, there is an abrupt switch from a state of high cyclin-dependent kinases (CDK) inhibitor (CKI) levels and low S-phase CDK activity to a state of high S-phase CDK activity and degraded CKI. In budding yeast, this transition is triggered by phosphorylation of the Cdk1 inhibitor Sic1 at multiple sites by G1-phase CDK (Cln1,2-Cdk1) and S-phase CDK (Clb5,6-Cdk1) complexes. Using mathematical modeling we demonstrate that the mechanistic basis for the abruptness of the G1/S transition is the highly specific phosphorylation of Sic1 by S-phase CDK complex. This switch is generated by a double-negative feedback loop in which S-CDK1 phosphorylates Sic1, thus targeting it for destruction, and thereby liberating further S-CDK1 from the inhibitory Sic1-S-CDK1 complex. Our model predicts that the abruptness of the switch depends upon a strong binding affinity within the Sic1-S-CDK inhibitory complex. In vitro phosphorylation analysis using purified yeast proteins revealed that free Clb5-Cdk1 can create positive feedback by phosphorylating Sic1 that is bound in the inhibitory complex, and that Sic1 inhibits Clb5-Cdk1 with a sub-nanomolar inhibition constant. Our model also predicts that if the G1-phase CDK complex is too efficient at targeting Sic1 for destruction, then G1/S becomes a smooth and readily reversible transition. We propose that the optimal role for the G1-phase CDK in the switch would not be to act as a kinase activity directly responsible for abrupt degradation of CKI, but rather to act as a priming signal that initiates a positive feedback loop driven by emerging free S-phase CDK.KEYWORDS: CDK; CKI; Cdk1; G1/S; Sic1; cyclin- switchPMID:
Inhibition of Clb5-Cdk1 and Cln2-Cdk1 by Sic1. (A) Autoradiograph of a Clb5-Cdk1 and Cln2-Cdk1 inhibition assay. Sic1 is extensively phosphorylated by Cln2-Cdk1 whereas no detectable phosphorylation is seen with Clb5-Cdk1. (B) Inhibition curves for Clb5-Cdk1 and Cln2-Cdk1 are presented as the initial rates of histone H1 phosphorylation in the presence of different concentrations of Sic1. (C) Calculated IC50 values from the experiment in panel (A). (D) The values of IC50 change in parallel with Clb5-Cdk1concentrations when both Sic1 and the kinase are varied in the picomolar or low nanomolar ranges.Front Physiol. .Sic1 is efficiently phosphorylated within the Sic1/Clb5-Cdk1 complex, when an excess of Clb5-Cdk1 is added. Assays with Cln2-Cdk1 complexes are included for comparison. (A) Autoradiography showing the phosphorylation of purified Sic1wt and Sic1ΔC by Clb5-Cdk1 and Cln2-Cdk1 complexes using 15 nM Sic1 and 30 nM cyclin-Cdk1 complexes. (B) The activity of Clb5-Cdk1 was determined using 2.5 μM histone H1, with and without 15 nM Sic1wt in the assay mixture. (C,D) Quantification of the experiment presented in panel (A). For comparison, phosphorylation rates were normalized using cyclin-Cdk1 activity units obtained in panel (B).Front Physiol. .Minimal model of the G1/S switch. Parameters used for diagrams and simulations presented in the figures below are listed in Tables
and . Black crosses designate the phospho-dependent degradation of Sic1 via the SCF-proteasome pathway. Gray crosses designate basal degradation of Sic1.Front Physiol. .Phase diagrams showing the bistability of the system at steady state. Parameter values are provided in Table . The dark gray arrows show possible paths for a gradual increase of free Clb5-Cdk1 while entering the S-phase, and possible reversible paths (light gray arrows) in the event of stochastic decreases in Clb5 levels. (A) Phase diagram showing the dependence of free Clb5-Cdk1 activity on total Clb5-Cdk1 levels. When a threshold is reached, the system switches itself into the state corresponding to S-phase, as indicated by the upward pointing arrow. (B) Phase diagram for the same system with the same parameter values as in panel (A), showing the dependence of total Sic1 concentration on total Clb5-Cdk1. The threshold level for a drop of Sic1 corresponds to the same threshold level of total Clb5-Cdk1 that triggers the jump in steady state levels of free Clb5-Cdk1 in panel (A).Front Physiol. .(A–D) The steady state phase diagrams showing the effect of the inhibition strength on the bistability of the G1/S switch. The dissociation rates of the inhibitory complex were increased in 10-fold increments from 0.01 to 10 min-1 as indicated. In the model, these values correspond to Ki values of 0.1–100 nM. Arrows indicate the paths of the system at the G1/S transition.Front Physiol. .(A–C) Phase diagrams showing the effect of changes in the relative ability of Cln2-Cdk1 to directly cause the degradation of Sic1. The rate constant values for Cln2-Cdk1 were gradually increased as indicated.Front Physiol. .Phase diagrams showing the potential effect of Cln2-dependent priming phosphorylation on the bistability of the system. The rate constant value of 0.001 nM×min-1 for Clb5-Cdk1 exemplifies a system with no Cln2-dependent priming while increasing values of this constant mimic increased levels of Cln2-dependent priming effect. (A) Phase diagrams showing the dependence of free Clb5-Cdk1 activity on total Clb5-Cdk1 levels. (B) Phase diagrams showing the dependence of total Sic1 concentration on total Clb5-Cdk1. The color coding is the same for both panels.Front Physiol. .Time course simulations to analyze the abruptness of the transition. The equation system and parameter values are provided in Table . (A) The simulation with the basic set of key parameters for inhibition and phosphorylation, similar to those used in the phase diagrams in Figure . (B) The effect of faster Cln2-dependent phosphorylation rate on the switch. The rate constant value for Cln2-Cdk1 was taken to be equal to the “k” value of Clb5-dependent phosphorylation. (C) The effect of weaker inhibition strength on the switch. The dissociation rate of the inhibitory complex was raised to 10 min-1, which in the model corresponds to a Ki value of 100 nM.Front Physiol. .Time course simulations showing the potential effect of Cln2-dependent priming phosphorylation on the abruptness of the switch. The equation system and parameter values are provided in Table . (A) A system with no priming effect in the absence of Cln2. The basal rate constant value of 0.001 nM-1 × min-1 for Clb5-Cdk1 was used. (B–D) Different priming effects were mimicked by using the following “k” values for Clb5-Cdk1: 0.01 nM-1 × min-1 (B), 0.03 nM-1 × min-1 (C), and 0.1 nM-1 × min-1 (D).Front Physiol. .Time course simulations for systems where only Cln2 is responsible for phosphorylation and degradation of Sic1. (A) A model similar to that in Figures
was used, except that the rate constant value for Clb5-Cdk1 toward Sic1 was taken to be zero. The rate constant for Cln2-Cdk1 was 0.001 nM-1 × min-1, which is the same value used for Clb5-Cdk1 in Figure . (B) A system that requires Cln2-dependent multisite phosphorylation for degradation of Sic1. The sequential phosphorylation of six sites in Sic1 was taken to be the output signal for degradation of Sic1.Front Physiol. .Full Text SourcesMolecular Biology DatabasesMiscellaneous
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