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PubMed2003

Cyclins and cyclin-dependent kinases: comparative study of hepatocellular carcinoma versus cirrhosis.

Increasing evidence has indicated that perturbation of cyclins is one of the major factors leading to cancer. The aim of this study was not only to investigate various cell cycle-related kinase activities in hepatocellular carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase activity levels between hepatitis C virus (HCV)-induced HCC and HCV-induced cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous cirrhosis were determined by Western blot. The enzymatic activities of cyclins D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and surrounding cirrhotic tissues. In addition, the protein levels and kinase activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 play an important role in the development of HCC from cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the histopathologic grade and progression of HCC.

Aged↗
PubMed2004

Construction of a cyclin D1-Cdk2 fusion protein to model the biological functions of cyclin D1-Cdk2 complexes.

Cyclin D1 is frequently overexpressed in human breast cancers, and cyclin D1 overexpression correlates with poor prognosis. Cyclin D1-Cdk2 complexes were previously observed in human breast cancer cell lines, but their role in cell cycle regulation and transformation was not investigated. This report demonstrates that Cdk2 in cyclin D1-Cdk2 complexes from mammary epithelial cells is phosphorylated on the activating phosphorylation site, Thr(160). Furthermore, cyclin D1-Cdk2 complexes catalyze Rb phosphorylation on multiple sites in vitro. As a model to investigate the biological and biochemical functions of cyclin D1-Cdk2 complexes, and the mechanisms by which cyclin D1 activates Cdk2, a cyclin D1-Cdk2 fusion gene was constructed. The cyclin D1-Cdk2 fusion protein expressed in epithelial cells was phosphorylated on Thr(160) and catalyzed the phosphorylation of Rb on multiple sites in vitro and in vivo. Kinase activity was not observed if either the cyclin D1 or Cdk2 domain was mutationally inactivated. Mutational inactivation of the cyclin D1 domain prevented activating phosphorylation of the Cdk2 domain on Thr(160). These results indicate that the cyclin D1 domain of the fusion protein activated the Cdk2 domain through an intramolecular mechanism. Cells stably expressing the cyclin D1-Cdk2 fusion protein exhibited several hallmarks of transformation including hyperphosphorylation of Rb, resistance to TGFbeta-induced growth arrest, and anchorage-independent proliferation in soft agar. We propose that cyclin D1-Cdk2 complexes mediate some of the transforming effects of cyclin D1 and demonstrate that the cyclin D1-Cdk2 fusion protein is a useful model to investigate the biological functions of cyclin D1-Cdk2 complexes.

Animals↗
PubMed2003

Expression of cyclin D3 and cyclin E and identification of distinct clusters of proliferation and apoptosis in diffuse large B-cell lymphomas.

In the present study 79 cases of de novo Diffuse Large B-cell Lymphomas (DLBCL) were studied in order: a) to analyse the expression of cyclin D3, cyclin E and cyclin D1 in relation to other proliferative features (expression of Ki67, cyclin A and cyclin B1), the apoptosis status and the expression of p53, Rb, p16 and p27; and b) to determine whether distinct clusters of proliferation and apoptosis could be identified in DLBCL. Overexpression of cyclin D3 and cyclin E was found in 35/79 (43%) and 18/79 (22%) cases, respectively, whereas overexpression of cyclin D1 was not detected in any case. In most cases (39/46) overexpression of cyclin D3 and cyclin E was mutually exclusive possibly reflecting different underlying pathways inducing deregulated expression of these cyclins. In most cases (29/35) overexpression of cyclin D3 was mutually exclusive with Rb/p16 aberrant expression status supporting an oncogenic role for cyclin D3 and suggesting that the pathogenetic effect of cyclin D3 overexpression occurs through perturbation of the Rb1 pathway. Combined alterations of the P53 and the Rb/p16/cyclin D3 expression status were significantly associated with higher mean values of cyclin A (p=0.023) and cyclin B1 (p=0.033) indicating that concurrent impairment of the p53 and Rb1 pathways induces increased tumour cell proliferation in DLBCL. Cluster analysis of the apoptosis and the proliferation status permitted separation of DLBCL into distinct groups with low (44 cases) and high (18 cases) apoptotic activity and into distinct groups with low (32 cases), intermediate (36 cases) and high (11 cases) proliferative activity. The identification of distinct clusters with respect to the proliferation and the apoptosis status indicates that groups with distinct cellular kinetic properties can be defined in the histological group of DLBCL.

Apoptosis↗
PubMed2002

Cyclin F is degraded during G2-M by mechanisms fundamentally different from other cyclins.

Cyclin F, a cyclin that can form SCF complexes and bind to cyclin B, oscillates in the cell cycle with a pattern similar to cyclin A and cyclin B. Ectopic expression of cyclin F arrests the cell cycle in G(2)/M. How the level of cyclin F is regulated during the cell cycle is completely obscure. Here we show that, similar to cyclin A, cyclin F is degraded when the spindle assembly checkpoint is activated and accumulates when the DNA damage checkpoint is activated. Cyclin F is a very unstable protein throughout much of the cell cycle. Unlike other cyclins, degradation of cyclin F is independent of ubiquitination and proteasome-mediated pathways. Interestingly, proteolysis of cyclin F is likely to involve metalloproteases. Rapid destruction of cyclin F does not require the N-terminal F-box motif but requires the COOH-terminal PEST sequences. The PEST region alone is sufficient to interfere with the degradation of cyclin F and confer instability when fused to cyclin A. These data show that although cyclin F is degraded at similar time as the mitotic cyclins, the underlying mechanisms are entirely distinct.

Cell Line↗
PubMed1992

Cyclin A-cdc2 kinase does not trigger but delays cyclin degradation in interphase extracts of amphibian eggs.

Purified cyclin B-cdc2 kinase has been shown previously to trigger cyclin degradation in interphase frog extracts by initiating a cascade of reactions that includes cyclin ubiquitinylation and ends with proteolysis. However, cyclin A-cdc2 kinase was not assayed in these early experiments. Here we have shown that full-length recombinant human cyclin A failed to induce cyclin degradation when it was added to frog extracts free of cyclin B, although it formed an active kinase complex with Xenopus cdc2. A highly purified kinase complex containing a truncated human cyclin A and starfish cdc2 also failed to switch on the cyclin degradation pathway. In contrast, both recombinant cyclin B and highly purified cyclin B-cdc2 kinase readily triggered degradation of both cyclins B and A in frog extracts. Whilst free cyclin A had no inhibitory effect, cyclin A-cdc2 kinase delayed degradation of both cyclins A and B induced by cyclin B-cdc2 kinase. The finding that cyclin A-cdc2 kinase cannot turn on, and even delays, cyclin destruction may be essential to prevent premature inactivation of MPF (maturation-promoting factor) before complete condensation of chromosomes and formation of the metaphase spindle.

Animals↗
PubMed1993

Differential effect of ionizing radiation on the expression of cyclin A and cyclin B in HeLa cells.

Ionizing radiation induces a G2 delay in eukaryotic cells. Since mitotic cyclins are required to trigger the transition from G2 into and through mitosis, we chose to investigate their expression after irradiation in HeLa cells. In normally cycling HeLa cells, both cyclin A and B mRNA and protein levels rise dramatically in G2/M and rapidly fall coincident with the completion of mitosis. The rise of cyclin A mRNA at the S/G2 boundary slightly precedes that of cyclin B mRNA. Although the peaks of expression of each of these molecules overlap, cyclin A mRNA and protein diminish before cyclin B. After irradiation in S, cyclin A mRNA and protein levels rose with the same kinetics as in the controls, but ultimately exceeded the levels seen in the control population. Cyclin A mRNA and protein levels remained high throughout the G2 delay induced by irradiation. In contrast, cyclin B mRNA and protein levels did not rise as the irradiated cells entered G2/M. Only later, before the irradiated cells exited from G2/M, did levels of cyclin B reach the levels seen in the unirradiated controls. The decreased amount of cyclin B mRNA and protein was inversely proportional to the dose of radiation. These data indicate that irradiation that results in a G2 delay appears to block cells at a point after production of cyclin A but before cyclin B can be fully expressed and that cells do not exit from the delay until cyclin B is again expressed. Thus, cyclin A and cyclin B expression respond differentially to radiation, with cyclin A rising at the same time as the control and to even higher levels than that seen in the controls, whereas cyclin B shows a temporal delay in expression.

Amino Acid Sequence↗
PubMed1998

In vivo regulation of cyclin A/Cdc2 and cyclin B/Cdc2 through meiotic and early cleavage cycles in starfish.

In starfish, fertilization occurs naturally at late meiosis I. In the absence of fertilization, however, oocytes complete meiosis I and II, resulting in mature eggs arrested at the pronucleus stage, which are still fertilizable. In this study, we isolated cDNAs of starfish cyclin A and Cdc2, and monitored extensively the cell cycle dynamics of cyclin A and cyclin B levels and their associated Cdc2 kinase activity, Tyr phosphorylation of Cdc2, and Cdc25 phosphorylation states throughout meiotic and early embryonic cleavage cycles in vivo. In meiosis I, cyclin A was undetectable and cyclin B/Cdc2 alone exhibited histone H1 kinase activity, while thereafter both cyclin A/Cdc2 and cyclin B/Cdc2 kinase activity oscillated along with the cell cycle. Cyclin B-, but not cyclin A-, associated Cdc2 was subjected to regulation via Tyr phosphorylation, and phosphorylation states of Cdc25 correlated with cyclin B/Cdc2 kinase activity with some exceptions. Between meiosis I and II and at the pronucleus stage, cyclin A and B levels remained low, Cdc2 Tyr phosphorylation was undetectable, and Cdc25 remained phosphorylated depending on MAP kinase activity, showing a good correlation between these two stages. Upon fertilization of mature eggs, Cdc2 Tyr phosphorylation reappeared and Cdc25 was dephosphorylated. In the first cleavage cycle, under conditions which prevented Cdc25 activity, cyclin A/Cdc2 was activated with a normal time course and then cyclin B/Cdc2 was activated with a significant delay, resulting in the delayed completion of M-phase. Thus, in contrast to meiosis I, both cyclin A and cyclin B appear to be involved in the embryonic cleavage cycles. We propose that regulation of cyclin A/Cdc2 and cyclin B/Cdc2 is characteristic of meiotic and early cleavage cycles.

Amino Acid Sequence↗
PubMed2005

Correlation between the expressions of gastrin, somatostatin and cyclin and cyclin-depend kinase in colorectal cancer.

AIM: To explore the correlation between the expressions of gastrin (GAS), somatostatin (SS) and cyclin, cyclin-dependent kinase (CDK) in colorectal cancer, and to detect the specific regulatory sites where gastrointestinal hormone regulates cell proliferation. METHODS: Seventy-nine resected large intestine carcinomatous specimens were randomly selected. Immunohistochemical staining for GAS, SS, cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2 and CDK4 was performed according to the standard streptavidin-biotin-peroxidase (S-P) method. According to the semi-quantitative integral evaluation, SS and GAS were divided into high, middle and low groups. Cyclin D1, cyclin E, cyclin A, cyclin B1, CDK2, CDK4 expressions in the three GAS and SS groups were assessed. RESULTS: The positive expression rate of cyclin D1 was significantly higher in high (78.6%, 11/14) and middle GAS groups (73.9%, 17/23) than in low GAS group (45.2%, 19/42) (P<0.05, c2(high vs low) = 4.691; P<0.05, c2(middle vs low) = 4.945). The positive expression rate of cyclin A was significantly higher in high (100%, 14/14) and middle GAS groups (82.6%, 19/23) than in low GAS group (54.8%, 23/42) (P<0.01, c2(high vs low) = 9.586; P<0.05, c2(middle vs low) = 5.040). The positive expression rate of CDK2 was significantly higher in high (92.9%, 13/14) and middle GAS groups (87.0%, 20/23) than in low GAS group (50.0%, 21/42) (P<0.01, c2(high vs low) = 8.086; P<0.01, c2(middle vs low) = 8.715). The positive expression rate of CDK4 was significantly higher in high (78.6%, 11/14) and middle GAS groups (78.3%, 18/23) than in low GAS group (42.9%, 18/42) (P<0.05, c2(high vs low) = 5.364; P<0.01, c2(middle vs low) = 7.539). The positive expression rate of cyclin E was prominently higher in low SS group (53.3%, 24/45) than in high (9.1%, 1/11) and middle (21.7%, 5/23) SS groups (P<0.05, c2(high vs low) = 5.325; P<0.05, c2(middle vs low) = 6.212). The positive expression rate of CDK2 was significantly higher in low SS group (77.8%, 35/45) than in high SS group (27.3%, 3/11) (P<0.01, c2(high vs low) = 8.151). There was a significant positive correlation between the integral ratio of GAS to SS and the semi-quantitative integral of cyclin D1, cyclin E, cyclin A, CDK2, CDK4 (P<0.05, (D1)r(s) = 0.252; P<0.01, (E)r(s) = 0.387; P<0.01, (A)r(s) = 0.466; P<0.01, (K2)r(s) = 0.519; P<0.01, (K4)r(s) = 0.434). CONCLUSION: The regulation and control of gastrin, SS in colorectal cancer cell growth may be directly related to the abnormal expressions of cyclins D1, A, E, and CDK2, CDK4. The regulatory site of GAS in the cell cycle of colorectal carcinoma may be at the G(1), S and G(2) phases. The regulatory site of SS may be at the entrance of S phase.

Adult↗
PubMed1996

Alternatively spliced cyclin C mRNA is widely expressed, cell cycle regulated, and encodes a truncated cyclin box.

The cyclin C protein has recently been shown to associate with a unique cyclin dependent protein kinase (cdk8) and it has been proposed that this complex may regulate RNA transcription during the cell cycle. In addition, the human cyclin C gene has been localized to human chromosome 6q21 and it was found to be frequently deleted in a subset of acute lymphoblastic leukemias (ALL's). Screening of an avian T-cell cDNA library resulted in the isolation of a cyclin C homologue as well as an abundant, yet distinct, cyclin C-related cDNA. The predicted open reading frame (ORF) of the cyclin C cDNA predicted a 283 amino acid protein that was > 99% identical to the human protein and 72% identical to the Drosophila melanogaster protein. However, the predicted ORF of the cyclin C-related cDNA predicted a much smaller 105 amino acid protein that was identical to cyclin C well into the cyclin-box region (amino acid residue 98), where it abruptly diverges and then terminates. Using PCR analysis of cDNA derived from a range of cell lines and tissues, alternative splicing of the avian cyclin C gene has been demonstrated. Furthermore, a smaller approximately 19 kDa protein that co-migrates with the in vitro transcribed and translated truncated cyclin C protein was detected in normal and virally-transformed avian cells with a cyclin C-specific antibody. Expression of alternatively spliced cyclin C mRNA and protein is regulated in a cell cycle-dependent manner reminiscent of cyclin B2. The function of this truncated cyclin C protein is not known, but its expression in avian cells suggest that this truncated cyclin C protein may participate as an early endogenously encoded cyclin C inhibitor.

Alternative Splicing↗
PubMed2002

Functional analysis of cyclin D2 and p27(Kip1) in cyclin D2 transgenic mouse mammary gland during development.

Two mammary gland phenotypes were detected in pregnant MMTV-cyclin D2 transgenic mice; line D2-53 exhibited a lack of alveologenesis and failure to nurse, whereas line D2-58 featured a reduction in alveologenesis, but retained normal nursing behavior. In pregnant mammary glands, cyclin D2 protein levels were twofold (P<0.107) and 3.8-fold (P<0.0076) higher in line D2-58 and D2-53, respectively, compared to wild type. Concomitantly with the increase in cyclin D2 was a fivefold decrease in cyclin D1 hyper-phosphorylated isoform in mammary glands of pregnant cyclin D2-58 mice. Because cyclin D1 is a critical molecule in normal mammary lobuloalveolar development, these data suggest that overexpression of cyclin D2 may block mammary lobuloalveolar development through inhibition of cyclin D1 phosphorylation. During mammary gland development, p27(kip1) protein level oscillated in a similar profile in wild type and cyclin D2 transgenic mice, but was consistently higher in the cyclin D2 mice suggesting that p27(kip1) functions downstream of cyclin D2. The ratio of p27(kip1)-cdk4/p27(kip1)-cdk2 was 6.5-fold (P<0.0003) higher in cyclin D2 mammary glands compared to wild type in pregnant animals. This ratio reversed to 2.2-fold (P<0.005) higher in wild type compared to cyclin D2 mammary glands in involution suggesting that overexpression of cyclin D2 moderately induced apoptosis during pregnancy but accelerated involution. Collectively, the effects of cyclin D2 overexpression on mammary gland development during pregnancy and involution are attributed to two major factors, altered p27(kip1) protein level and inhibition of cyclin D1 phosphorylation.

Animals↗
PubMed2003

Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors.

A novel method employing filter arrays of a cDNA expression library for the identification of substrates for protein kinases was developed. With this technique, we identified a new member of the cyclin family, cyclin L2, as a substrate of the nuclear protein kinase DYRK1A. Cyclin L2 contains an N-terminal cyclin domain and a C-terminal arginine/serine-rich domain (RS domain), which is a hallmark of many proteins involved in pre-mRNA processing. The gene for cyclin L2 encodes the full-length cyclin L2, which is predominantly expressed in testis, as well as a truncated splicing variant (cyclin L2S) that lacks the RS domain and is ubiquitously expressed in human tissues. Full-length cyclin L2, but not cyclin L2S, was associated with the cyclin-dependent kinase PITSLRE. Cyclin L2 interacted with splicing factor 2 in vitro and was co-localized with the splicing factor SC35 in the nuclear speckle compartment. Photobleaching experiments showed that a fusion protein of green fluorescent protein and cyclin L2 in nuclear speckles rapidly exchanged with unbleached molecules in the nucleus, similar to other RS domain-containing proteins. In striking contrast, the closely related green fluorescent protein-cyclin L1 was immobile in the speckle compartment. DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. These data characterize cyclin L2 as a highly mobile component of nuclear speckles and suggest that DYRK1A may regulate splicing by phosphorylation of cyclin L2.

Amino Acid Sequence↗
PubMed2006

Skp2 contains a novel cyclin A binding domain that directly protects cyclin A from inhibition by p27Kip1.

Skp2 is well known as the F-box protein of the SCF(Skp2) x Roc1 complex targeting p27 for ubiquitylation. Skp2 also forms complexes with cyclin A, which is particularly abundant in cancer cells due to frequent Skp2 overexpression, but the mechanism and significance of this interaction remain unknown. Here, we report that Skp2-cyclin A interaction is mediated by novel interaction sequences on both Skp2 and cyclin A, distinguishing it from the well known RXL-hydrophobic patch interaction between cyclins and cyclin-binding proteins. Furthermore, a short peptide derived from the mapped cyclin A binding sequences of Skp2 can block Skp2-cyclin A interaction but not p27-cyclin A interaction, whereas a previously identified RXL peptide can block p27-cyclin A interaction but not Skp2-cyclin A interaction. Functionally, Skp2-cyclin A interaction is separable from Skp2 ability to mediate p27 ubiquitylation. Rather, Skp2-cyclin A interaction serves to directly protect cyclin A-Cdk2 from inhibition by p27 through competitive binding. Finally, we show that disruption of cyclin A binding with point mutations in the cyclin A binding domain of Skp2 compromises the ability of overexpressed Skp2 to counter cell cycle arrest by a p53/p21-mediated cell cycle checkpoint without affecting its ability to cause degradation of cellular p27 and p21. These findings reveal a new functional mechanism of Skp2 and a new regulatory mechanism of cyclin A.

Amino Acid Motifs↗
PubMed1995

Threshold expression of cyclin E but not D type cyclins characterizes normal and tumour cells entering S phase.

Complexes of cyclin-dependent kinases (cdk) and their partner cyclins drive the cell through the cell cycle, each such complex phosphorylating a distinct set of proteins at a particular check-point or phase of the cycle. Immunocytochemical detection of cyclins combined with measurement of cellular DNA content by flow cytometry makes it possible to relate expression of each of these proteins with the actual cell cycle position, without the necessity of cell synchronization. In the present study, we have investigated expression of E and D type cyclins in G1 cells and in cells entering S phase, in eight different human hematopoietic and solid tumour cell lines (two leukaemias, a lymphoma, three breast carcinomas, a colon carcinoma and a bladder transitional cell carcinoma) during their exponential phase of growth, as well as in normal mitogen stimulated lymphocytes. In all the cell types studied, the average level of D type cyclin expression was invariable throughout the cell cycle. A great intercellular variability, in particular of the G1 cell subpopulations, and the presence of a large fraction of G1, S and G2 + M cells that were cyclin D negative (20-40% in tumour cell lines and about 80% among lymphocytes), were other characteristic features of D type cyclin expression. In contrast to D type cyclins, the expression of cyclin E was discontinuous during the cycle, peaking at the time of cell entrance to S. Also, a well defined threshold in expression of cyclin E characterized cells that were entering S phase, and virtually no cyclin E negative cells were seen during the early portion of S phase. The data indicate that while cell entrance to S phase is unrelated to expression of D type cyclins (at the time of entrance), accumulation of cyclin E up to critical level is a prerequisite for initiation of DNA replication. The great intercellular variability in expression of D type cyclins and their invariant average level across the cell cycle suggest that these cyclins, in addition to their acknowledged function in promoting cell progression through mid- to late-G1 may have other role(s), related or unrelated to the cell cycle progression. The presence of a large number of D type cyclin negative cells in all phases of the cycle suggests that during exponential growth the cells may not express this protein and yet may traverse the cycle, including G1 phase.

Blotting, Western↗
PubMed2003

Expression of p27, cyclin E and cyclin A in hepatocellular carcinoma and its clinical significance.

AIM: To investigate the expression of p27, cyclin E and cyclin A in hepatocellular carcinoma (HCC) and its potential clinical significance. METHODS: Expression of p27, cyclin E and cyclin A in 45 HCC specimens and 30 adjacent noncancerous lesions obtained from 45 patients during surgery was examined by immunohistochemical SABC assay. The diameter of tumor ranged from 1 cm to 19 cm (d< or =5 cm, 9 samples; 5 cm 10 cm, 17 samples). The tumors were graded according to the criteria described by Edmondson-Steiner: well-differentiated HCC group (Grade I+II), 26 samples; poorly-differentiated HCC group (Grade III+IV), 19 samples. According to the clinical-pathologic features, 19 samples were poorly encapsulated, 15 samples had portal invasion of cancer, 11 samples had extrahepatic metastasis, and 12 samples had intrahepatic metastasis. All of the samples were classified as the invasive and metastatic group, while the remaining was classified as the non-invasive and non- metastatic group. RESULTS: The average labeling index (LI) of p27 in HCC lesions was significantly higher than that in adjacent noncancerous lesions (45.87+/-14.21 vs 33.77+/-12.92, t=3.745, P<0.001). The LI of p27 was associated with differentiation, invasiveness and metastasis of the tumors (34.46+/-12.29 vs 52.80+/-11.36, t=5.17; 41.42+/-12.86 vs 51.44+/-14.10, t=2.48; P<0.05). Cyclin E was overexpressed in 16 cases (35.6%) while cyclin A was overexpressed in 21 cases (46.7%) in HCC lesions. No overexpression of cyclin E or cyclin A could be observed in adjacent non-carcinoma lesions and normal liver tissues. The overexpressions of cyclin E and cyclin A were correlated with differentiation, tumor thrombus, invasiveness and metastasis (P<0.05). Expression of cyclin E was significantly correlated with expression of cyclin A (r=0.329, P<0.05). The LI of p27 was significantly decreased in cyclin E, cyclin A positive groups (40.33+/-11.91 vs 49.50+/-13.76, t=3.05; 38.86+/-11.19 vs 52.57+/-12.62, t=3.89; P<0.05). CONCLUSION: p27, cyclin E, cyclin A play cooperative roles in HCC tumorigenesis, differentiation, invasiveness and metastasis. Detection of their expression may be helpful in prediction of tumor progression.

Adult↗
PubMed2000

Overexpression of cyclin A and cyclin B1 proteins in astrocytomas.

BACKGROUND: Cyclins are proteins that are expressed during the progression of a normal cell through the cell cycle. In a number of cancers, overexpression of cyclin A and cyclin B1 proteins has been reported, and in some instances the levels of expression correlated well with the grades of malignancy. The expression of cyclin A and cyclin B1 proteins in astrocytoma may be linked to the histologic grade or proliferative activities. OBJECTIVE: To study the expression of cyclin A and cyclin B1 proteins in astrocytomas and correlate the labeling indices (LIs) of cyclin A and cyclin B1 with histologic grade and Ki-67 LI. DESIGN: The surgical biopsy specimens from 65 adults with astrocytomas were reviewed and divided into grades based on the World Health Organization system. The paraffin sections were immunostained using primary antibodies against Ki-67, cyclin A, and cyclin B1. The LIs of these astrocytomas for the 3 different antibodies were determined by computerized image analysis. RESULTS: The cyclin A LI showed good correlation with astrocytoma grade and Ki-67 LI. Both the nuclear and cytoplasmic cyclin B LIs correlated well with the tumor grade but showed poor correlation with Ki-67 LI. CONCLUSIONS: This study suggests that although both cyclin A and B protein expression are related to the grade of malignancy in astrocytomas, cyclin A levels more generally reflect the proliferative state of these tumors. We also provide indirect evidence that cyclin B1 is associated with the aberrant progression through the G2-M phase checkpoint in astrocytomas.

Astrocytoma↗
PubMed1997

Cyclin D1 expression in mantle cell lymphoma is accompanied by downregulation of cyclin D3 and is not related to the proliferative activity.

The cell cycle regulatory protein cyclin D1 is essential for G1-S phase transition in several epithelial and mesenchymal tissues but is apparently not essential in normal mature B cells. An overexpression of cyclin D1 is induced by the chromosomal translocation t(11;14)(q13;q32), which characterizes non-Hodgkin's lymphomas (NHLs) of mantle cell type. We studied 26 cases of mantle cell lymphoma (MCL) for the expression of cyclins D1 and D3. A total of 23 lymphomas showed a nuclear staining for cyclin D1, whereas reactive B cells of residual germinal centers were constantly negative. When compared with cyclin D3, an inverse staining pattern emerged. Whereas the B cells of residual germinal centers reacted strongly positive for cyclin D3, there was low or missing expression of cyclin D3 in MCL cells. In other B-cell lymphomas (n = 55), including chronic lymphocytic leukemia, low-grade lymphomas of mucosa-associated lymphatic tissue, follicular lymphomas, and diffuse large B-cell lymphomas, no cyclin D1 expression could be detected and 89% of these cases displayed cyclin D3 positivity. Lymphoma cell lines harboring the t(11;14) showed cyclin D1 protein but no or very low levels of cyclin D3; three other B-cell lines, a T-cell line, and peripheral blood lymphocytes strongly expressed cyclin D3 and reacted negatively for cyclin D1. We conclude that the chromosomal translocation t(11;14) leads to an abnormal protein expression of cyclin D1 in the tumor cells of MCL and induces a consecutive downregulation of cyclin D3. In contrast to other B-NHLs, cyclin D1 and D3 expression in MCL is not related to the growth fraction.

Cell Division↗
PubMed1997

Expression of cyclin D1, but not cyclins E and A, is related to progression in bilharzial bladder cancer.

The present study was conducted to analyze the alterations affecting cyclins D1, E, and A in bilharzial bladder cancer and to assess their potential clinical significance. A total of 125 cases were examined. Histopathological subtypes included 68 squamous cell carcinomas, 55 transitional cell carcinomas, and 2 adenocarcinomas. Immunohistochemical analyses were performed using a panel of well-characterized antibodies. The results were correlated with proliferative index, as assessed by Ki67 antigen expression. The cyclin D1-positive phenotype, defined as the identification of positive immunoreactivity in the nuclei of >/=20% of tumor cells, was found in 33 of 107 (31%) evaluable cases. A significant association was observed between the cyclin D1-positive phenotype and deep muscle invasion (P = 0.02), high tumor grade (P = 0.02), and Ki67 high proliferative index (P = 0.03). The cyclin E-positive phenotype, defined as per cyclin D1, was found in 79 of 106 (75%) evaluable cases. The cyclin A-positive phenotype, defined using the above criteria, was identified in 60 of 108 (56%) evaluable cases. No statistically significant association was found between cyclins E or A and clinicopathological parameters or proliferative index. However, there was a strong association between the expression of cyclin D1 and the coexpression of cyclins A and/or E (P = 0.05). Ki67 proliferative index was considered high when >/=20% of tumor cells displayed positive nuclear staining, a phenotype that was observed in 99 of 115 (86%) cases. These data support the hypothesis that cyclin D1 activation determines the evolution of a particular subset of aggressive bladder tumors. In addition, cyclins E and A seem to follow an unscheduled pattern of expression, based on the high frequency of identifying a positive phenotype for these cyclins and the lack of correlation between their expression and Ki67 high proliferative index. It may be postulated that the expression of G1 cyclin genes is deregulated in bilharzial bladder cancer, and that cyclin D1 acts as an oncogenic event in these neoplasms. Moreover, the moderate number of tumors displaying the cyclin D1-positive phenotype (31%) versus the high frequency observed for both cyclins E (75%) and A (56%), suggests a short G1 disbalanced by a long S phase and a rapid transversal of the cell cycle, as evidenced by a high Ki67 index observed in 86% of these cases. This imbalance in the cell cycle, together with alterations reported on the p53 pathway, might underline the accumulation of DNA damage and the aggressive clinical course of bilharzial bladder cancer.

Adenocarcinoma↗
PubMed2004

Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, Cyclin D1, and Cyclin D3) and proliferation index (ki67-MIB1).

OBJECTIVE: To determine the prognostic value of a subset of regulators of the transition from G1-to-S phase of cell cycle in stage T1 grade 3 bladder cancers. METHODS: Fifty-one such cases were investigated to determine the significance on patient's survival of p53, p21Waf1, p27Kip1, Cyclin D1, Cyclin D3, and ki67-MIB1 (proliferation index). The statistical analysis included Kaplan-Meier methodology with Log-rank test and Cox' proportional hazard analysis. RESULTS: Tumor size (p=0.0034), and the labeling index of ki67-MIB1 (p=0.0034), p53 (p=0.0332), p27kip1 (p=0.0059) and Cyclin D1 (p=0.0103) were associated to disease-free survival. Progression-free survival was related to tumor size (p<0.0001), ki67 (p=0.0163), p53 (p=0.0041), p27kip1 (p=0.0161), Cyclin D1 (p<0.0001) and Cyclin D3 (p<0.0001). Patient's overall survival was associated to Cyclin D3 (p<0.0001), p53 (p=0.0017), p21Waf1 (p=0.0142), Cyclin D1 (p<0.0001), ki67-MIB1 (p=0.0450), and tumor size (p=0.0296). Down-regulation of p27kip1 and Cyclin D3 over-expression (disease-free), over-expression of p53, Cyclin D1 and Cyclin D3 (progression-free), and over-expression of Cyclin D3 (overall survival) were independent predictors by Cox's multivariate analysis. Down-regulation of p27kip1 (p<0.001, R.R. 0.997, 95%C.I. 0.995-0.999), and over-expression of Cyclin D1 (p<0.001, R.R. 1.009, 95%C.I. 1.004-1.014) and Cyclin D3 (p=0.005, R.R. 1.013, 95%C.I. 1.004-1.022) were the main independent predictors. CONCLUSION: Down-regulation of p27kip1 and over-expression of Cyclin D1 and Cyclin D3 might be relevant predictors of survival in stage T1 grade 3 bladder cancers, thus selecting a group of patients at higher risk of malignant behavior.

Adjuvants, Immunologic↗