Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cyclins”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed2002

Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin.

In B-cell chronic lymphocytic leukemia (B-CLL), malignant cells seem to be arrested in the G(0)/early G(1) phase of the cell cycle, and defective apoptosis might be involved in disease progression. However, increasing evidence exists that B-CLL is more than a disease consisting of slowly accumulating resting B cells: a proliferating pool of cells has been described in lymph nodes and bone marrow and might feed the accumulating pool in the blood. Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human B cells, and has shown activity against a broad range of human tumor cell lines. Therefore, we investigated the ability of rapamycin to block cell cycle progression in proliferating B-CLL cells. We have recently demonstrated that stimulation with CpG-oligonucleotides and interleukin-2 provides a valuable model for studying cell cycle regulation in malignant B cells. In our present study, we demonstrated that rapamycin induced cell cycle arrest in proliferating B-CLL cells and inhibited phosphorylation of p70s6 kinase (p70(s6k)). In contrast to previous reports on nonmalignant B cells, the expression of the cell cycle inhibitor p27 was not changed in rapamycin-treated leukemic cells. Treatment with rapamycin prevented retinoblastoma protein (RB) phosphorylation in B-CLL cells without affecting the expression of cyclin D2, but cyclin D3 was no longer detectable in rapamycin-treated B-CLL cells. In addition, rapamycin treatment inhibited cyclin-dependent kinase 2 activity by preventing up-regulation of cyclin E and cyclin A. Interestingly, survivin, which is expressed in the proliferation centers of B-CLL patients in vivo, is not up-regulated in rapamycin-treated cells. Therefore, rapamycin interferes with the expression of many critical molecules for cell cycle regulation in cycling B-CLL cells. We conclude from our study that rapamycin might be an attractive substance for therapy for B-CLL patients by inducing a G(1) arrest in proliferating tumor cells.

Aged↗
PubMed2004

Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery.

Prostate cancer is the second leading cause of cancer-related deaths in males in the United States. This warrants the development of novel mechanism-based strategies for the prevention and/or treatment of prostate cancer. Several studies have shown that plant-derived alkaloids possess remarkable anticancer effects. Sanguinarine, an alkaloid derived from the bloodroot plant Sanguinaria canadensis, has been shown to possess antimicrobial, anti-inflammatory, and antioxidant properties. Previously, we have shown that sanguinarine possesses strong antiproliferative and proapoptotic properties against human epidermoid carcinoma A431 cells and immortalized human HaCaT keratinocytes. Here, employing androgen-responsive human prostate carcinoma LNCaP cells and androgen-unresponsive human prostate carcinoma DU145 cells, we studied the antiproliferative properties of sanguinarine against prostate cancer. Sanguinarine (0.1-2 micromol/L) treatment of LNCaP and DU145 cells for 24 hours resulted in dose-dependent (1) inhibition of cell growth [as evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], (2) arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis), and (3) induction of apoptosis (as evaluated by DNA ladder formation and flow cytometry). To define the mechanism of antiproliferative effects of sanguinarine against prostate cancer, we studied the effect of sanguinarine on critical molecular events known to regulate the cell cycle and the apoptotic machinery. Immunoblot analysis showed that sanguinarine treatment of both LNCaP and DU145 cells resulted in significant (1) induction of cyclin kinase inhibitors p21/WAF1 and p27/KIP1; (2) down-regulation of cyclin E, D1, and D2; and (3) down-regulation of cyclin-dependent kinase 2, 4, and 6. A highlight of this study was the fact that sanguinarine induced growth inhibitory and antiproliferative effects in human prostate carcinoma cells irrespective of their androgen status. To our knowledge, this is the first study showing the involvement of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery during cell cycle arrest and apoptosis of prostate cancer cells by sanguinarine. These results suggest that sanguinarine may be developed as an agent for the management of prostate cancer.

Alkaloids↗
PubMed2003

Arabidopsis D-type cyclin CYCD4;1 is a novel cyclin partner of B2-type cyclin-dependent kinase.

B-type cyclin-dependent kinases (CDKs) are unique to plants and are assumed to be involved in the control of the G2-to-M phase progression and mitotic events. However, little is known about their cyclin partners. In Arabidopsis, we isolated cDNA encoding the D-type cyclin CYCD4;1 by a yeast (Saccharomyces cerevisiae) two-hybrid screening using CDKB2;1 as bait. In vitro pull-down assay showed that CYCD4;1 bound to CDKB2;1 and CDKA;1. Protein complexes of CYCD4;1-CDKA;1 and CYCD4;1-CDKB2;1 in insect cells exhibited histone H1-kinase activity. Promoter analysis using the luciferase reporter gene showed that CDKB2;1 was expressed from early G2 to M phase, whereas CYCD4;1 was expressed throughout the cell cycle. In situ hybridization of plant tissues revealed that both CDKB2;1 and CYCD4;1 transcripts accumulated in the shoot apical meristem, leaf primordia, vasculature of leaves, and tapetal cells in anthers. Our results suggest that CDKB2;1 and CYCD4;1 may form an active kinase complex during G2/M phase and control the development of particular tissues.

Arabidopsis↗
PubMed2002

Analysis of Drosophila cyclin EI and II function during development: identification of an inhibitory zone within the morphogenetic furrow of the eye imaginal disc that blocks the function of cyclin EI but not cyclin EII.

The Drosophila cyclin E (DmcycE) gene gives rise to two transcripts encoding proteins that differ at their N termini, DmcycEII and DmcycEI. This study presents the first in vivo dissection of Cyclin E function. Ectopic expression studies using N- and C-terminal deletions of DmcycEI revealed that a region of 322 residues surrounding the cyclin box is sufficient to induce entry of G1-arrested larval eye imaginal disc cells into S phase. Ectopic expression of DmcycEI in the eye disc has been previously shown to drive anterior, but not posterior, G1-phase cells within the morphogenetic furrow (MF) into S phase. Significantly, ectopic expression of DmcycEII and N-terminal deletions of DmcycEI were able to drive all G1 cells within the morphogenetic furrow into S phase, while a C-terminal deletion of DmcycEI could not. The p21 homolog Dacapo was shown by yeast two-hybrid, coimmunolocalization, and in vivo functional studies not to be the mediator of the DmcycEI inhibition in posterior part of the MF. Taken together, these results reveal a novel zone within the posterior region of the MF where DmcycEI but not DmcycEII function is inhibited, and suggest that DmcycEII is a more potent inducer of S phase.

Animals↗
PubMed1993

Mechanisms that help the yeast cell cycle clock tick: G2 cyclins transcriptionally activate G2 cyclins and repress G1 cyclins.

In budding yeast, G1 cyclins such as CLN1 and CLN2 are expressed in G1 and S phases, while mitotic cyclins such as CLB1 and CLB2 are expressed in G2 and M phases. We find that the CLBs play a central role in the transition from CLNs to CLBs: the CLBs stimulate their own expression while repressing that of CLNs. This negative regulation of CLNs may occur via the transcription factor SWI4, because CLBs are necessary for G2 repression of SCB-regulated genes like CLN1 and CLN2 but not for repression of MCB-regulated genes like DNA polymerase and CLB5. Furthermore, SW14 associates with CLB2 protein and is a substrate for the CLB2-associated CDC28 kinase in vitro.

Activity Cycles↗
PubMed2002

Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells.

Cyclin D1 and cyclin E are overexpressed in approximately 45% and 30% of breast cancers, respectively, and adverse associations with patient outcome have been reported. The potential roles of cyclin D1 and cyclin E expression as markers of therapeutic responsiveness to the pure steroidal antiestrogen ICI 182780 were investigated using T-47D breast cancer cell lines constitutively overexpressing cyclin D1 or cyclin E. Measurement of S phase fraction, phosphorylation states of the retinoblastoma protein, and cyclin E-cyclin-dependent kinase (Cdk) 2 activity demonstrated that overexpression of cyclin D1 decreased sensitivity to antiestrogen inhibition at 24 and 48 h. Overexpression of cyclin E produced a less pronounced early cell cycle effect indicating only partial resistance to antiestrogen inhibition in the short-term. In ICI 182780-treated cyclin D1-overexpressing cells, sufficient Cdk activity was retained to allow retinoblastoma protein phosphorylation and cell proliferation, despite an increase in the association of p21 and p27 with cyclin D1-Cdk4/6 and cyclin E-Cdk2 complexes. After longer-term (>7 days) treatment, antiestrogens inhibited colony growth in cyclin D1- or cyclin E-overexpressing breast cancer cells, but with an approximately 2-2.5-fold decrease in dose sensitivity. This was associated with a fall in cyclin D1 levels, a reduction in the half-life of cyclin D1 protein and a decline in cyclin E-Cdk2 activity in cyclin D1-overexpressing cells, and the maintenance of cyclin E-p27 association in the cyclin E-overexpressing cells. These data confirm that cyclin D1 expression and cyclin E-p27 association play important roles in antiestrogen action, and suggest that cyclin D1 or cyclin E overexpression has subtle effects on antiestrogen sensitivity. Additional studies to elucidate the contribution of alterations in cyclin D1 stability to antiestrogen action and to assess the relationship between antiestrogen sensitivity and expression of cyclin D1, cyclin E, or p27 in a clinical setting are required.

Breast Neoplasms↗
PubMed1996

Activation of the Xenopus cyclin degradation machinery by full-length cyclin A.

The entry into mitosis is dependent on the activation of mitotic forms of cdc2 kinase. In many cell types, cyclin A-associated kinase activity peaks just prior to that of cyclin B, although the precise role of cyclin A-associated kinase in the entry into mitosis is still unclear. Previous work has suggested that while cyclin B is capable of triggering cyclin destruction in Xenopus cell-free systems, cyclin A-associated kinase is not able to support this function. Here we have expressed a full-length human cyclin A in Escherichia coli and purified the protein to homogeneity by virtue of an N-terminal histidine tag. We have found that when added to Xenopus cell-free extracts free of cyclin B and incapable of protein synthesis, the temporal pattern of cyclin A-associated cdc2 kinase activity showed distinct differences that were dependent on the concentration of cyclin A added. When cyclin A was added to a concentration that generated levels of cdc2 kinase activity capable of inducing nuclear envelope breakdown, the histone H1 kinase activity profile was bi-phasic, consisting of an activation phase followed by an inactivation phase. Inactivation was found to be due to cyclin destruction, which was prevented by mos protein. Cyclin destruction was followed by nuclear reassembly and an additional round of DNA replication, indicating that there is no protein synthesis requirement for DNA replication in this embryonic system. It has been suggested that the evolutionary recruitment of cyclin A into an S phase function may have necessitated the loss of an original mitotic ability to activate the cyclin destruction pathway. The results presented here indicate that cyclin A has not lost the ability to activate its own destruction and that cyclin A-mediated activation of the cyclin destruction pathway permitted destruction of cyclin B1 as well as cyclin A, indicating that there are not distinct cyclin A and cyclin B destruction pathways. Thus the ordered progression of the cell cycle requires the careful titration of cyclin. A concentration in order to avoid activation of the cyclin destruction pathway before sufficient active cyclin B/cdc2 kinase has accumulated.

Animals↗
PubMed1999

Aberrant expression of cyclin A and cyclin B1 proteins in oral carcinoma.

Cyclins play an important role in regulating the passage of dividing cells through critical checkpoints in the cell cycle. Aberrant expression of cyclin proteins has been found in a number of human cancers, including carcinomas of the head and neck, where amplification of the cyclin D1 gene is a common finding. The objective of this study was to examine cell cycle kinetics in oral carcinomas by determining the expression of the S phase protein cyclin A and the M phase protein cyclin B1. Routinely processed tissue sections of 50 oral squamous cell carcinomas from the floor of the mouth were stained by immunohistochemistry for cyclin A, cyclin B1 and Ki-67 proteins. Ten specimens of normal epithelium from the floor of the mouth were used as controls. The number of cells showing nuclear staining for cyclin A, cyclin B1 and Ki-67 proteins was determined by computer image analysis. There were 17 well-differentiated, 25 moderately differentiated and 8 poorly differentiated tumours. Mean counts for cyclin A (29.50+/-4.10, mean+/-95% CI), cyclin B1 (2.05+/-0.30) and Ki-67 (49.46+/-5.91) proteins in the carcinomas were significantly higher than counts for the normal epithelial controls (cyclin A: 9.30+/-1.72; cyclin B1: 1.01+/-0.36; Ki-67: 17.40+/-4.17). For cyclin A, cyclin B1 and Ki-67, mean staining scores for all tumour grades were significantly higher than controls. There was a strong correlation between Ki-67 and cyclin A scores in all tumour groups (r2=0.68); however, the correlations between cyclin B1 and cyclin A scores (r2=0.35) and between cyclin B1 and Ki-67 scores (r2= 0.39) were weak. We conclude that there is overexpression of cyclin A and cyclin B1 proteins in oral carcinoma. Furthermore, the poor correlations for cyclin B1 scores with other cell cycle indices suggest that there may be aberrant cell cycle progression at the G2/M checkpoint in oral carcinomas.

Carcinoma, Squamous Cell↗
PubMed2001

Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27(Kip1) association with cyclin E-Cdk2.

Long-term growth inhibition, arrest in G(1) phase and reduced activity of both cyclin D1-Cdk4 and cyclin E-Cdk2 are elicited by progestin treatment of breast cancer cells in culture. Decreased cyclin expression, induction of p18(INK4c) and increased association of the CDK inhibitors p21(WAF1/Cip1) and p27(Kip1) with cyclin E-Cdk2 have been implicated in these responses. To determine the role of decreased cyclin expression, T-47D human breast cancer cells constitutively expressing cyclin D1 or cyclin E were treated with the progestin ORG 2058. Overexpression of cyclin E had only a modest effect on growth inhibition. Although cyclin E expression was maintained during progestin treatment, cyclin E-Cdk2 activity decreased by approximately 60%. This was accompanied by p27(Kip1) association with cyclin E-Cdk2, indicating that both cyclin E down-regulation and p27(Kip1) recruitment contribute to the decrease in activity. In contrast, overexpression of cyclin D1 induced progestin resistance and cell proliferation continued despite decreased cyclin E-Cdk2 activity. Progestin treatment of cyclin D1-overexpressing cells was associated with increased p27(Kip1) association with cyclin E-Cdk2. Thus the ability of cyclin D1 to confer progestin resistance does not depend on sequestration of p27(Kip1) away from cyclin E-Cdk2, providing evidence for a critical function of cyclin D1 other than as a high-capacity "sink" for p27(Kip1). These data indicate that regulation of cyclin D1 is a critical element of progestin inhibition in breast cancer cells and suggest that breast cancers overexpressing cyclin D1 may respond poorly to progestin therapy.

Animals↗
PubMed1999

Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.

BACKGROUND: Cyclin-dependent kinases (CDKs) have a central role in cell-cycle control and are activated by complex formation with positive regulatory proteins called cyclins and by phosphorylation. The overexpression and mutation of cyclins and CDKs has been associated with tumorigenesis and oncogenesis. A virus-encoded cyclin (v-cyclin) from herpesvirus saimiri has been shown to exhibit highest sequence homology to type D cyclins and specifically activates CDK6 of host cells to a very high degree. RESULTS: We have determined the first X-ray structure of a v-cyclin to 3.0 A resolution. The structure of the core domains is very similar to those of cyclin A and cyclin H from human cells. To understand the structural basis for the v-cyclin specificity for CDK6 and the insensitivity of the complex to inhibitors of the p21 and INK4 families, a v-cyclin-CDK2 model was built on the basis of the known structures of human cyclin A in complex with CDK2 and the CDK inhibitor p27(Kip1). CONCLUSIONS: Although many critical interactions between cyclin A and CDK2 would be conserved in a v-cyclin-CDK2 complex, some appear sterically or electrostatically unfavorable due to shifts in the backbone conformation or sidechain differences and may contribute to v-cyclin selectivity for CDK6. The insensitivity of v-cyclin-CDK6 complexes to inhibitors of the p21 family is probably due to structural changes in v-cyclin that lead to a flatter surface area offering fewer potential contacts with the protein inhibitor. In addition, sequence changes in v-cyclin eliminate hydrogen-bonding partners for atoms of the p27(Kip1) inhibitor. This structure provides the first model for interactions between v-cyclins and host cell-cycle proteins; these interactions may be important for virus survival as well as oncogenic transformation of host cells.

Amino Acid Sequence↗
PubMed2005

Cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors: detection methods and activity measurements.

The cyclin/cyclin-dependent kinase (Cdk) complexes and the Cdk inhibitors (CDKI) are crucial regulators of cell cycle progression in all eukaryotic cells. Using rat cardiac myocytes as a model system, this chapter provides a detailed account of methods that can be employed to measure both cyclin/Cdk activity in cells and the extent of CDKI inhibitory activity present in a particular cell type.

Animals↗
PubMed2000

Levels of cyclin D1 and D3 in malignant melanoma: deregulated cyclin D3 expression is associated with poor clinical outcome in superficial melanoma.

We examined 172 primary (110 superficial and 62 nodular) and 73 metastatic melanomas, as well as 10 benign nevi, for protein expression of cyclin D1 and cyclin D3 and evaluated the relationship between deregulated protein levels and clinical outcome. For both proteins, a heterogeneous nuclear staining pattern was observed. Cyclin D3 was expressed by 96% of primary and 97% of metastatic melanomas. The corresponding percentages for cyclin D1 were 62% and 29%, respectively. In benign nevi, only rare cyclin D3-positive cells and no cyclin D1-positive cells were observed. High levels of cyclin D3 (>5% of the cells stained) were detected in 26 of 62 (42%) nodular melanomas and in 22 of 110 (20%) superficial tumors, whereas no such difference was observed with respect to cyclin D1. In superficial melanomas, a significant concordant staining pattern was observed between cyclin D1 and cyclin D3 (P = 0.0009), cyclin D1 and Ki-67 (P = 0.0001), cyclin D1 and cyclin A (P = 0.02), cyclin D3 and Ki-67 (P < 0.00001), and cyclin D3 and cyclin A (P = 0.002). Kaplan-Meier analysis revealed that high levels of cyclin D3 were an indicator of early relapse and decreased overall survival for patients with superficial (P = 0.001 and P = 0.009, respectively) but not nodular (P = 0.64 and P = 0.23) melanoma. Cyclin D1 did not have any impact on disease-free and overall survival for either of the subtypes. In conclusion, our results suggest that deregulation of cyclin D3 expression leading to increased proliferation may be a prognostic factor for superficial melanoma, whereas deregulated cell cycle machinery seems to have little impact on disease progression of nodular melanoma.

Biomarkers, Tumor↗
PubMed2007

Cyclin A2 regulates nuclear-envelope breakdown and the nuclear accumulation of cyclin B1.

Mitosis is thought to be triggered by the activation of Cdk-cyclin complexes. Here we have used RNA interference (RNAi) to assess the roles of three mitotic cyclins, cyclins A2, B1, and B2, in the regulation of centrosome separation and nuclear-envelope breakdown (NEB) in HeLa cells. We found that the timing of NEB was affected very little by knocking down cyclins B1 and B2 alone or in combination. However, knocking down cyclin A2 markedly delayed NEB, and knocking down both cyclins A2 and B1 delayed NEB further. The timing of cyclin B1-Cdk1 activation was normal in cyclin A2 knockdown cells, and there was no delay in centrosome separation, an event apparently controlled by the activation of cytoplasmic cyclin B1-Cdk1. However, nuclear accumulation of cyclin B1-Cdk1 was markedly delayed in cyclin A2 knockdown cells. Finally, a constitutively nuclear cyclin B1, but not wild-type cyclin B1, restored normal NEB timing in cyclin A2 knockdown cells. These findings show that cyclin A2 is required for timely NEB, whereas cyclins B1 and B2 are not. Nevertheless cyclin B1 translocates to the nucleus just prior to NEB in a cyclin A2-dependent fashion and is capable of supporting NEB if rendered constitutively nuclear.

Cell Nucleus↗
PubMedDate not supplied

Immunolocalization of cyclins D and E and cyclin dependent kinase (cdk) 2 and 4 in human breast carcinoma.

We studied the immunolocalization of cyclins D1 and E and their corresponding partner cyclin dependent kinases (cdk), cdk4 and cdk2 in 41 cases of human breast malignancy (21 invasive ductal carcinomas and 19 invasive lobular carcinomas) and examined the correlation of the labeling indexes among these cyclins, cdks, Ki67, estrogen receptor (ER) and progesterone receptor (PR). Cyclin D1 immunoreactivity was observed exclusively in the nuclei of tumor cells in 27/41 (65%) of the cases examined. Immunoreactivity for cyclin E and cdk2 was detected in all the cases and observed in the nuclei of both carcinoma and non-carcinoma cells. cdk4 immunoreactivity was detected in 39/41 (95%) cases and found in carcinoma and non-carcinoma cells. In all carcinomas examined, a significant correlation was observed only between Ki67 and cyclin D1 (p = 0.0037). However, when examining only invasive ductal carcinomas, a significant correlation was detected between Ki67 and cyclin D1 (p = 0.0069), Ki67 and cdk2 (p = 0.0043) and cyclin D1 and cdk4 (P = 0.0024). Only cyclin D1 correlated with the pathologic stages of the disease and histological grades of invasive ductal carcinoma. Among these cyclins and cdk, overexpression of cyclin D1 is considered to play an important role in the development of human breast malignancy through abnormal proliferation. No significant correlation was observed between steroid receptor status and any of cyclins and cdks examined. Cyclin D1 and cdk2 expression correlated with cell proliferation (Ki67) and cyclin D1 expression with expression of cdk4 in invasive ductal carcinoma but not invasive lobular carcinoma. Cyclin E expression did not correlate with cell proliferation, cyclin D1 or cdks possibly due to deregulation of its expression. These results also indicate different patterns of cyclin D1, cyclin E, cdk2 and cdk4 expression between invasive ductal and lobular carcinoma of human breast.

Breast Neoplasms↗
PubMed2006

Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis.

D-type cyclins are components of the cell-cycle engine that link cell signaling pathways and passage throughout G1 phase. We previously described the effects of overexpression cyclin D1, D2 or D3 in mouse epidermis and tumor development. We now asked whether cyclin D2 and/or cyclin D3 play a relevant role in ras-dependent tumorigenesis. Here, we described the effect of cyclin D3 and cyclin D2 overexpression in mouse skin tumor development. Notably, overexpression of cyclin D3 results in reduced tumor development and malignant progression to squamous cell carcinomas (SCC). Biochemical analysis of keratinocytes shows that overexpression of cyclin D3 results in strong reduction of cyclin D2 and its associated kinase activity. Furthermore, we found that reinstatement of cyclin D2 level in the cyclin D3/cyclin D2 bigenic mice results in a complete reversion of the inhibitory action of cyclin D3. Supporting these results, ablation of cyclin D2 results in reduced tumorigenesis and malignant progression. On the other hand, overexpression of cyclin D2 results in an increased number of papillomas and malignant progression. We conclude that cyclin D3 and cyclin D2 play opposite roles in mouse skin tumor development and that the suppressive activity of cyclin D3 is associated with cyclin D2 downregulation.

Animals↗
PubMed2005

Cyclin G1 overcomes radiation-induced G2 arrest and increases cell death through transcriptional activation of cyclin B1.

Although cyclin G1 has been implicated in certain p53-related biological phenomena, other aspects of its function remain unclear. Here we report hitherto unknown mechanism by which cyclin G1 increases radiation sensitivity by regulating the level of cyclin B1. Overexpression of cyclin G1 was observable in lung carcinoma tissues. Irradiation of human lung cells with cyclin G1 overexpression resulted in increased cell death and gamma-H2AX foci suggesting that cyclin G1 rendered the cells more susceptible to DNA damage. Enhanced radiosensitivity by cyclin G1 was correlated with increased cyclin B1, CDC2/cyclin B1 complex, and MPM2. Cell cycle synchronization clearly showed coexpression of cyclin G1 and cyclin B1 in G2/M phase. Depletion of cyclin G1 by interference RNA revealed that cyclin G1 regulated transcription of cyclin B1 in a p53-independent manner, and confirmed that the increased mitotic cells and cell death by cyclin G1 were dependent upon cyclin B1. Therefore, our data suggest that cyclin G1 enhanced radiation sensitivity by overriding radiation-induced G2 arrest through transcriptional upregulation of cyclin B1.

Adenocarcinoma, Papillary↗
PubMed2005

A study on the prognostic value of cyclins D1 and E expression levels in resectable gastric cancer and on some correlations between cyclins expression, histoclinical parameters and selected protein products of cell-cycle regulatory genes.

Cyclins condition the course of a cell cycle through the activation of appropriate serine-threonine kinases. Any variation in the cyclins' expression result in pathologies of the cell division, including neoplastic proliferation. Activity of the complexes of cyclins D1 and E with appropriate cyclin-dependent kinases may be inhibited by protein P21 (WAF1/CIP1) which functions as a cell growth cycle inhibitor. As yet, there have been rather few reports on the prognostic value of this cyclin expression assessment in gastric cancer, the kind of neoplasm still characterized by very poor prognosis. The study aimed at the assessment of expression levels of cyclins D1 and E in surgically removed gastric cancers, including the analysis of this prognostic value parameter, and attempted to determine some correlations between the expression of the examined cyclins and selected histoclinical and molecular parameters such as: patients' age and gender, histological type according to the Lauren classification, cancer stage (TNM), degree of histological malignancy (G) and level of expression of the cell-cycle regulatory genes protein products--P53, P21, P27. Immunohistochemical analysis was performed on specimens obtained from radical stomach resections of 80 patients treated in the period 1992-1997 for gastric cancer stage I-IIIB (TNM-UICC) at the Department of Surgical Oncology, Medical University of Lodz. For immunohistochemical examinations, the LSAB system was used, designed for assessment of antigen expression. In statistical analysis, Fisher's exact test was applied to evaluate correlations between the analyzed variables and Mantel-Haenschel's test to evaluate their collinearity. For the evaluation of the effect of the analyzed variables on postoperation survival and recurrence-free survival the Cox regression model was used. When analyzing the prognostic value and survival period in association to the cyclins D1 and E expression levels, a statistically significant correlation was found only in relation to cyclin E expression: a survival period of minimum 5 year duration was significantly higher in the group displaying a negative, or only faintly positive, reaction to the presence of cyclin E, than in the group with a strongly positive response. Moreover, the analysis showed statistically significant non-linear dependence between the histological type of cancer in the Lauren classification as well as a degree of histological malignancy and the level of cyclin E expression, and a negative correlation between the level of cyclin E expression and the stage of cancer; In addition, a positive correlation between the level of P53 and cyclin E expression as well as statistically significant non-linear correlation between the level of cyclin E expression and the level of protein P21 expression was observed. However, no statistically significant correlations were found between the level of expression of the two cyclins and the level of protein P27 expression or between the levels of cyclin D1 and E expression in gastric cancer. Out of the two types of evaluated cyclins only cyclin E can be considered a significant regulatory factor and a useful prognostic parameter in gastric cancer.

Cell Cycle↗
PubMed2003

Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression.

The activation of CDK2-cyclin E in late G1 phase has been shown to play a critical role in retinoblastoma protein (pRb) inactivation and G1-S phase progression of the cell cycle. The phosphatidylinositol 3-OH-kinase inhibitor LY294002 has been shown to block cyclin D1 accumulation, CDK4 activity and, thus, G1 progression in alpha-thrombin-stimulated IIC9 cells (Chinese hamster embryonic fibroblasts). Our previous results show that expression of cyclin E rescues S phase progression in alpha-thrombin-stimulated IIC9 cells treated with LY294002, arguing that cyclin E renders CDK4 activity dispensable for G1 progression. In this work we investigate the ability of alpha-thrombin-induced CDK2-cyclin E activity to inactivate pRb in the absence of prior CDK4-cyclin D1 activity. We report that in the absence of CDK4-cyclin D1 activity, CDK2-cyclin E phosphorylates pRb in vivo on at least one residue and abolishes pRb binding to E2F response elements. We also find that expression of cyclin E rescues E2F activation and cyclin A expression in cyclin D kinase-inhibited, alpha-thrombin-stimulated cells. Furthermore, the rescue of E2F activity, cyclin A expression, and DNA synthesis by expression of E can be blocked by the expression of either CDK2(D145N) or RbDeltaCDK, a constitutively active mutant of pRb. However, restoring four known cyclin E-CDK2 phosphorylation sites to RbDeltaCDK renders it susceptible to inactivation in late G1, as assayed by E2F activation, cyclin A expression, and S phase progression. These data indicate that CDK2-cyclin E, without prior CDK4-cyclin D activity, can phosphorylate and inactivate pRb, activate E2F, and induce DNA synthesis.

Animals↗