Cyclin D1与细胞周期调控

细胞周期是细胞生命活动中一个最重要的过程,其关键是G1 期的启动.细胞周期蛋白(Cyclin)、细胞周期蛋白依赖性激酶(CDKs)和CDK抑制因子(CKIs)是参与钿胞周期调控的主要因子.Cyclin D1是调控细胞周期G1期的关键蛋白,是一个比其他Cyclins更加敏感的指标,对细胞周期调控至关重要.综述Cyclin D1的结构和功能及其在肿瘤组织中的表达特征,初步分析Cyclin D在昆虫细胞周期调控的研究.     

Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy

The myocytes of the adult mammalian heart are considered unable to divide. Instead, mitogens induce cardiomyocyte hypertrophy. We have investigated the effect of adenoviral overexpression of cyclin D2 on myocyte proliferation and morphology. Cardiomyocytes in culture were identified by established markers. Cyclin D2 induced DNA synthesis and proliferation of cardiomyocytes and impaired hypertrophy induced by angiotensin II and serum. At the molecular level, cyclin D2 activated CDK4/6 and lead to pRB phosphorylation and downregulation of the cell cycle inhibitors p21Waf1/Cip1 and p27Kip1. Expression of the CDK4/6 inhibitor p16 inhibited proliferation and cyclin D2 overexpressing myocytes became hypertrophic under such conditions. Inhibition of hypertrophy by cyclin D2 correlated with downregulation of p27Kip1. These data show that hypertrophy and proliferation are highly related processes and suggest that cardiomyocyte hypertrophy is due to low amounts of cell cycle activators unable to overcome the block imposed by cell cycle inhibitors. Cell cycle entry upon hypertrophy may be converted to cell division by increased expression of activators such as cyclin D2.     

Cyclin E2 is required for embryogenesis in Xenopus laevis

In mammalian cells, E-type cyclins (E1 and E2) are generally believed to be required for entry into S phase. However, in mice, cyclin E is largely dispensable for normal embryogenesis. Moreover, Drosophila cyclin E plays a critical role in cell fate determination in neural lineages independently of proliferation. Thus, the functions of cyclin E, particularly during early development, remain elusive. Here, we investigated the requirement for E-type cyclins during Xenopus embryogenesis. Although cyclin E1 has been reported as a maternal cyclin, inhibition of its translation in the embryo caused no serious defects. We isolated a Xenopus homologue of human cyclin E2, which was zygotically expressed. Sufficient inhibition of its expression led to death at late gastrula, while partial inhibition allowed survival. These observations indicate distinct roles for Xenopus cyclins E1 and E2, and an absolute requirement of cyclin E2 for Xenopus embryogenesis.     

中药固真方对UMR106细胞周期蛋白表达及细胞周期的影响

应用流式细胞技术和 Western blot技术 ,观察了中药固真方对大鼠成骨肉瘤细胞 UMR1 0 6细胞的细胞周期及细胞周期蛋白 cyclin E和 cyclin A表达的影响 .结果显示 :固真方处理 UMR1 0 6细胞后 2 4 h,S期细胞百分比达高峰 ,占 49.6% ,而对照组 30 h时 ,S期细胞才增高 ,达 43.2 % .cy-clin E的表达在固真方处理 8h时增高 ,而对照组在 1 6h时 ,cyclin E表达才达高峰 .cyclin A的表达在给药组处理 2 4 h时最高 ,而对照组在 30 h时 ,cyclin A表达才增高 .揭示固真方可缩短细胞周期的时程 ,加速细胞周期的运行 ,从而促进细胞增殖 .     

Molecular Cloning of a Cell Cycle Regulation Gene Cyclin H from Ischemic Rat Brain

Gene expression plays an important role in determining the fate of neurons after ischemia. To identify additional genes that promote survival or execute programmed cell death in ischemic neurons, a subtractive cDNA library was constructed from hippocampus of rats subjected to global ischemia. With use of a differential screening technique, a cDNA was identified that was up-regulated after ischemia. The cDNA was found to have high homology with human cyclin H at both the nucleotide level (89%) and the amino acid level (93%). Northern blotting detected cyclin H mRNA in nonischemic and ischemic brains. In situ hybridization studies revealed that cyclin H message was found in hippocampal neurons in nonischemic brain. After ischemia, expression was increased primarily in the dentate gyrus and CA3 regions of hippocampus. Expression of cyclin H protein, detected by western blotting of hippocampal tissue, was increased after global ischemia, but expression of cyclins B1 and D1 and other related cell cycle genes (Cdk7 and Cdc2) was not increased. Cyclin H immunoreactivity was found exclusively within neurons. After ischemia, there was increased immunoreactivity within neurons in dentate gyrus, CA3, and cortex. Thus, cyclin H is expressed in normal postmitotic neurons and expression is increased in neurons that are ischemic yet survive. These results suggest that cyclin H may have functions in neurons other than cell cycle regulation, including other known functions such as DNA repair.     

Cyclin D1 Immunoreactivity in Meningiomas

Objective Cyclin D1 is an important nuclear protein required for progression of cells through the G1 phase of the cell cycle. The proliferative potential of meningiomas has been studied using various proliferative markers. However, there have been only few published studies evaluating Cyclin D1 immunoreactivity in meningiomas. Purpose of the study The aim of our study was to analyze the Cyclin D1 expression in meningiomas and correlate it both with proliferation markers Ki67 and PCNA, and with meningiomas of WHO grade. Material and methods We evaluated immunoreactivity for proliferative markers (Cyclin D1, Ki-67, and PCNA) in a consecutive series of 64 meningioma samples obtained from patients who underwent surgical resection because of cerebral or spinal meningiomas. Immunohistochemical staining with Ki-67, PCNA, and Cyclin D1 was performed using the microwave processing procedure and LSAB+ methodology. The number of positive cells for each antibody has been determined and shown in percentage in relation to 1000 counted cells. Results All meningioma samples showed immunostaining for Ki-67, PCNA, and Cyclin D1 antibodies. The Cyclin D1 scores exhibited a close correlation with Ki-67 and PCNA immunostaining (P < 0.01). Some meningiomas (15 cases) showed a combination of nuclear and cytoplasmatic (fine granular) Cyclin D1 immunoreactivity. All proliferative indexes have been in positive correlation with meningioma grade. Conclusion Our comparative study of proliferative markers in meningiomas demonstrated Cyclin D1 as a very useful proliferative marker in meningiomas.     

Human Cdc25A phosphatase has a non-redundant function in G2 phase by activating Cyclin A-dependent kinases

Cdc25 phosphatases activate Cdk/Cyclin complexes by dephosphorylation and thus promote cell cycle progression. We observed that the peak activity of Cdc25A precedes the one of Cdc25B in prophase and the maximum of Cyclin/Cdk kinase activity. Furthermore, Cdc25A activates both Cdk1-2/Cyclin A and Cdk1/Cyclin B complexes while Cdc25B seems to be involved only in activation of Cdk1/Cyclin B. Concomitantly, repression of Cdc25A led to a decrease in Cyclin A-associated kinase activity and attenuated Cdk1 activation. Our results indicate that Cdc25A acts before Cdc25B - at least in cancer cells, and has non-redundant functions in late G2/early M-phase as a major regulator of Cyclin A/kinase complexes.     

Repression of Cyclin D1 Expression Is Necessary for the Maintenance of Cell Cycle Exit in Adult Mammalian Cardiomyocytes

The hearts of neonatal mice and adult zebrafish can regenerate after injury through proliferation of preexisting cardiomyocytes. However, adult mammals are not capable of cardiac regeneration because almost all cardiomyocytes exit their cell cycle. Exactly how the cell cycle exit is maintained and how many adult cardiomyocytes have the potential to reenter the cell cycle are unknown. The expression and activation levels of main cyclin-cyclin-dependent kinase (CDK) complexes are extremely low or undetectable at adult stages. The nuclear DNA content of almost all cardiomyocytes is 2C, indicating the cell cycle exit from G₁-phase. Here, we induced expression of cyclin D1, which regulates the progression of G1-phase, only in differentiated cardiomyocytes of adult mice. In these cardiomyocytes, S-phase marker-positive cardiomyocytes and the expression of main cyclins and CDKs increased remarkably, although cyclin B1-CDK1 activation was inhibited in an ATM/ATR-independent manner. The phosphorylation pattern of CDK1 and expression pattern of Cdc25 subtypes suggested that a deficiency in the increase in Cdc25 (a and -b), which is required for M-phase entry, inhibited the cyclin B1-CDK1 activation. Finally, analysis of cell cycle distribution patterns showed that >40% of adult mouse cardiomyocytes reentered the cell cycle by the induction of cyclin D1. The cell cycle of these binucleated cardiomyocytes was arrested before M-phase, and many mononucleated cardiomyocytes entered endoreplication. These data indicate that silencing the cyclin D1 expression is necessary for the maintenance of the cell cycle exit and suggest a mechanism that involves inhibition of M-phase entry.     

Cyclin E expression during development in Caenorhabditis elegans

Our interest in the coordination of cell cycle control and differentiation has led us to investigate the Caenorhabditis elegans cye-1 gene encoding the G(1) cell cycle regulator cyclin E. We have studied the expression and function of cye-1 by using monoclonal antibodies directed against CYE-1 protein, cye-1::GFP reporter genes, and a cye-1 chromosomal deletion mutation. We show that a ubiquitous embryonic pattern of expression becomes restricted and dynamic during postembryonic development. Promoter analysis reveals a relatively small region of cis-acting sequences that are necessary for the complex pattern of expression of this gene. Our studies demonstrate that two other G(1) cell cycle genes, encoding cyclin D and CDK4/6, have similarly compact promoter requirements. This suggests that a relatively simple mechanism of regulation may underlie the dynamic developmental patterns of expression exhibited by these three G(1) cell cycle genes. Our analysis of a new cye-1 deletion allele confirms and extends previous studies of two point mutations in the gene.     

肝癌组织中CyclinD1及其相关基因研究的进展

细胞周期调控异常会导致肿瘤的发生和发展，CyclinD1是细胞周期的重要调控元件之一，与肝癌发生、进展及预后关系密切。本文就CyclinD1的结构、功能、作用机制、肝癌组织中CyclinD1及其相关基因研究的进展情况予以综述。     

Fertilization initiates the transition from anaphase I to metaphase II during female meiosis in C. elegans

Oocytes from most animals arrest twice during the meiotic cell cycle. The universally conserved prophase I arrest is released by a maturation hormone that allows progression to a second arrest point, typically metaphase I or II. This second arrest allows for short-term storage of fertilization-competent eggs and is released by signaling that occurs during fertilization. Nematodes are unique in that the maturation hormone is secreted by sperm rather than by the mother's somatic tissues. We have investigated the nature of the second arrest in matured but unfertilized Caenorhabditis elegans embryos using time-lapse imaging of GFP-tubulin or GFP-histone. Unfertilized embryos completed anaphase I but did not form polar bodies or assemble meiosis II spindles. Nevertheless, unfertilized embryos assembled female pronuclei at the same time as fertilized embryos. Analysis of embryos fertilized by sperm lacking the SPE-11 protein indicated that fertilization promotes meiotic cytokinesis through the SPE-11 protein but assembly of the meiosis II spindle is initiated through an SPE-11-independent pathway.     

CyclinD1在鲍温病中的表达

目的:探讨cyclinD1(细胞周期蛋白D1)在鲍温病皮肤组织中的表达及其临床意义。方法:采用免疫组化S-P法观察16例鲍温病标本中cyclinD1的表达模式。结果:正常人皮肤组织中,cyclinD1阳性细胞主要分布在基底层及毛囊漏斗部的基底层细胞上。在16例鲍温病标本中14例细胞核内cyclinD1过度表达,阳性细胞分布于肿瘤组织。结论:cyclinD1的异常表达可能与鲍温病的发生相关。     

Paradoxical roles of cyclin D1 in DNA stability

Maintenance of DNA integrity is vital for all of the living organisms. Consequence of DNA damaging ranges from, introducing harmless synonymous mutations, to causing disease-associated mutations, genome instability, and cell death. A cell cycle protein cyclin D1 is an established cancer-driving protein. However, contribution of cyclin D1 to cancer formation and cancer survival is not entirely known. In cancer tissues, overexpression of cyclin D1 is associated with both cancer genome instability, and resistance to DNA-damaging cancer drugs. Emerging evidence indicated that cyclin D1 may play novel direct roles in regulating DNA repair. Here we provide an insight how cyclin D1 expression may contribute to DNA repair and chromosome instability, and how these functions may facilitate cancer formation, and drug resistance.     

Global cell sorting in the C. elegans embryo defines a new mechanism for pattern formation

4D microscopic observations of Caenorhabditis elegans development show that the nematode uses an unprecedented strategy for development. The embryo achieves pattern formation by sorting cells, through far-ranging movements, into coherent regions before morphogenesis is initiated. This sorting of cells is coupled to their particular fate. If cell identity is altered by experiment, cells are rerouted to positions appropriate to their new fates even across the whole embryo. This cell behavior defines a new mechanism of pattern formation, a mechanism that is also found in other animals. We call this new mechanism "cell focusing". When the fate of cells is changed, they move to new positions which also affect the shape of the body. Thus, this process is also important for morphogenesis.     

Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells

The regulation of D-type cyclin-dependent kinase activity is critical for neuronal differentiation and apoptosis. We recently showed that cyclin D1 is sequestered in the cytoplasm and that its nuclear localization induces apoptosis in postmitotic primary neurons. Here, we further investigated the role of the subcellular localization of cyclin D1 in cell cycle withdrawal during the differentiation of N1E-115 neuroblastoma cells. We show that cyclin D1 became predominantly cytoplasmic after differentiation. Targeting cyclin D1 expression to the nucleus induced phosphorylation of Rb and cdk2 kinase activity. Furthermore, cyclin D1 nuclear localization promoted differentiated N1E-115 cells to reenter the cell cycle, a process that was inhibited by p16(INK4a), a specific inhibitor of D-type cyclin activity. These results indicate that cytoplasmic sequestration of cyclin D1 plays a role in neuronal cell cycle withdrawal, and suggests that the abrogation of machinery involved in monitoring aberrant nuclear cyclin D1 activity contributes to neuronal tumorigenesis.