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Results for “Cyclin E”

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At least 19 recordsLinked to original sources

PubMed2003

Expressions of cyclin E, cyclin dependent kinase 2 and p57(KIP2) in human gastric cancer.

OBJECTIVE: To investigate the expressions of cyclin E, cyclin dependent kinase 2 (CDK-2) and cyclin-dependent kinase inhibitor p57(KIP2) in human gastric cancer, and to evaluate the relationships between protein levels and clinicopathological parameters. METHODS: Western blot was used to measure the expressions of cyclin E, CDK-2 and p57(KIP2) proteins in the surgically resected gastric carcinoma, adjacent normal mucosa and metastatic lymph nodes from 36 patients. RESULTS: Cyclin E and CDK-2 protein levels were higher in gastric cancer tissues in comparison with normal tissues (P < 0.05). Overexpression of cyclin E was correlated with lymph node involvement, poor histological grade and serosa invasion (P < 0.05). Overexpression of CDK-2 was correlated with lymph nodes involvement (P < 0.05). No statistically significant difference between cyclin E and CDK-2 expression was found when samples were stratified according to tumor size (P > 0.05). Expression of cyclin E and CDK-2 showed a positive linear correlation (r = 0.451, P = 0.01). Protein levels of p57(KIP2) were lower in gastric cancer tissues than in the normal mucosa (P < 0.05). Decreased expression of p57(KIP2) was correlated with lymph node involvement (P < 0.05). No statistically significant difference in p57(KIP2) expression was found when sample were stratified according to tumor size, histological grade or serosa invasion (P > 0.05). In metastatic lymph nodes, expression of cyclin E was increased and the expression of p57(KIP2) decreased. CONCLUSION: Overexpressions of cyclin E, CDK-2 and downregulated expression of p57(KIP2) may play important roles in tumorigenesis and metastatic potential of gastric cancer.

Blotting, Western↗

PubMed1999

Retinoic acid prevents phosphorylation of pRB in normal human B lymphocytes: regulation of cyclin E, cyclin A, and p21(Cip1).

The mechanisms underlying the growth-inhibitory effect of retinoids on normal human B lymphocytes are not well understood. We addressed this issue by examining the effect of retinoic acid on the cell cycle machinery involved in G1/S transition. When retinoic acid was administered to B cells stimulated into mid to late G1 by anti-IgM antibodies (anti-mu) and Staphylococcus aureus crude cell suspension (SAC), the phosphorylation of pRB required for S-phase entry was prevented in a time- and dose-dependent manner. Thus, 2-hour treatment with retinoic acid at the optimal concentration of 1 micromol/L prevented phosphorylation of pRB, and effects were noted at concentrations as low as 10 nmol/L. Based on our results, we suggest that the rapid effect of retinoic acid on pRB phosphorylation is due primarily to the reduced expression of cyclin E and cyclin A in late G1. This could lead to the diminished cyclin E- and cyclin A-associated kinase activities noted as early as 2 hours after addition of retinoic acid. Furthermore, our results imply that the transient induction of p21(Cip1) could also be involved. Thus, retinoic acid induced a rapid, but transient increased binding of p21(Cip1) to CDK2. The retinoic acid receptor (RAR) agonist TTNPB mimicked the key events affected by retinoic acid, such as pRB phosphorylation, cyclin E expression, and expression of p21(Cip1), whereas the RAR-selective antagonist Ro 41-5253 counteracted the effects of retinoic acid. This implies that retinoic acid mediates its growth-inhibitory effect on B lymphocytes via the nuclear receptors.

B-Lymphocytes↗

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↗

PubMed1994

Alternative splicing of human cyclin E.

Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry, thus defining it as a G1 cyclin. We report here the existence of a 43 kDa splice variant of human cyclin E, termed cyclin Es, which lacks 49 amino acids within the cyclin box compared to the known 48 kDa cyclin E. Cyclin Es is expressed at approximately 1/10 of the level of full-length cyclin E in several cell lines analysed. The two cyclin E forms differ functionally in that cyclin E, but not cyclin Es, is able to complex with cdk2, to activate the histone H1, pRb and p107 in vitro kinase activity of cdk2 and to rescue a triple CLN mutation in S. cerevisiae. Cyclin Es is the first splice variant of a cell cycle regulatory protein to be described. Our findings also indicate that the cyclin box in cyclin E mediates the interaction with cdk2.

Alternative Splicing↗

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↗

PubMed1994

Inducible acceleration of G1 progression through tetracycline-regulated expression of human cyclin E.

Cyclin E is a cell cycle-regulated protein that activates the cdc2-related protein kinases cdk2 shortly before S-phase entry. In order to analyse the biological role of cyclin E, we have generated HeLa cells that allow the conditional expression of ectopic human cyclin E. In these cells, a cyclin E cDNA is under the control of a bacterial tetracycline repressor-VP16 activator hybrid protein. In the absence of tetracycline, the endogenous gene becomes activated and leads to the synthesis of elevated levels of cyclin E. Concomitant with this increase in cyclin E expression we show by a combined time-lapse video recording/5-bromo-deoxyuridine labelling procedure a significant acceleration of G1 transition by approximately 1.5 hours. This observation is consistent with the idea that cyclin E is a rate-limiting factor with respect to the control of G1-->S transition. The experimental system described here should also prove useful to address the function of cyclin E in further detail.

Cyclins↗

PubMed2001

Reciprocal expressions of cyclin E and cyclin D1 in hepatocellular carcinoma.

Deregulation of the cell cycle by overexpression of G1 cyclins, cyclin E and cyclin D1 genes, has been demonstrated to be a prerequisite for the development of human cancer. Recently, cyclin E is proposed to be sufficient for the progression of the G1 cell cycle without cyclin D1. Here we show that the proposed model system was specifically present in human hepatocellular carcinoma (HCC) unlike other human cancers. Of 31 HCC tissues analyzed, 21 (67.7%) exhibited an overexpression of cyclin E protein. In contrast to cyclin E gene expression, cyclin D1 expression was strongly downregulated in 19 (61.2%) HCCs. Interestingly, 65% of HCC tissues with overexpression of the cyclin E gene exhibited downregulation of cyclin D1, suggesting reciprocal deregulation of these cyclins in the G1 progression of the cell cycle. Southern blot analysis proved the amplification of cyclin E gene in HCC with a high level of overexpression. The present findings suggest that the reciprocal deregulation of cyclin E lacking cyclin D1 expression might play a role in G1 progression and the development of HCC.

Blotting, Southern↗

PubMed1998

Role of cyclin E and cyclin E-dependent kinase in mitogenic stimulation by cementum-derived growth factor in human fibroblasts.

Cementum-derived growth factor (CGF) is a 14 kDa polypeptide sequestered in tooth cementum. It is an IGF-I like molecule that is weakly mitogenic to fibroblasts, but its mitogenic action is synergistically potentiated in the presence of epidermal growth factor (EGF) or serum. We have examined whether the CGF affects cyclin E levels and the activity of cyclin-dependent kinase (Cdk) associated with this cyclin, and whether these changes contribute to the synergism in mitogenic activity between CGF and EGF. Optimal DNA synthesis by serum-starved human gingival fibroblasts required the presence of CGF for 0-12 h and EGF for 0-3 h. Therefore, cells were serum starved for 48 h and then exposed to CGF, EGF, or CGF + EGF. Cells incubated with 10% fetal bovine serum (FBS) served as positive controls. At various time points after the addition of growth factors, cyclin E levels were examined by Western analysis. Cdk associated with cyclin E was immunoprecipitated with anti-cyclin E antibody and kinase activity was measured using H1 histone as substrate. Cyclin E and the H1 kinase activity levels increased after 8-12 h in cells exposed to CGF and in positive controls exposed to 10% FBS. They returned to basal level 4 h later in cells exposed to CGF alone, whereas in the presence of CGF + EGF and FBS they remained elevated for up to 20 h. The cyclin E levels did not increase in the presence of EGF alone. Cyclin-dependent kinase inhibitors p21cip1 and p27kip1 were barely detectable in these cells. Fibroblasts transfected with LXSN-cyclin E, a retroviral vector containing cyclin E cDNA, overexpressed cyclin E and their steady-state cyclin E-Cdk activity was higher than control cells. DNA synthesis by cyclin E overexpressing cells was higher, but optimal DNA synthesis by these cells required the presence of CGF and EGF. These results show that CGF action involves an increase in the levels of cyclin E and E-Cdk activity and that the higher levels are maintained in the presence of both CGF and EGF. They also indicate that sustained high cyclin E levels and Cdk2 activity during G1 phase are necessary, but not sufficient, for optimal mitogenic response in human fibroblasts.

Animals↗

PubMed2001

Expression of cyclin E and cyclin D1 in non-small cell lung cancers.

The relationships between overexpression of cyclin D1 or cyclin E and clinicopathological factors were investigated in 157 patients with non-small cell lung cancers (NSCLCs) using immunohistochemical analysis. Fifty-eight cases of NSCLCs (58/157, 37%) showed the overexpression of cyclin D1, and 64 cases (64/157, 41%) were positive for cyclin E. Cyclin E and cyclin D1 were infrequently concurrently overexpressed (17/157, 10.8%). Overexpression of cyclin E was more frequently observed in squamous cell carcinoma (29/57, 51%) compared with that in adenocarcinoma (28/86, 33%) (P<0.05). In addition, overexpression of cyclin E was more frequently observed in poorly or moderately differentiated NSCLCs (52/103, 50%) than in well-differentiated ones (12/54, 22%) regardless of their histological types (P<0.01). On the contrary, there was no statistically significant relationship between cyclin D1 overexpression and histological types or grade of tumor differentiation. These findings suggest that expression of cyclin E was frequently independent of that of cyclin D1 and played some roles in the grade of tumor differentiation in NSCLCs.

Adult↗

PubMed1995

Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation.

To investigate E7-dependent biochemical changes which are involved in cellular transformation, we analyzed the influence of human papillomavirus type 16 (HPV-16) E7 on the expression of cell cycle regulatory proteins. Expression of E7 in established rodent fibroblasts (NIH 3T3), which was shown to be sufficient for transformation of these cells, leads to constitutive expression of the cyclin E and cyclin A genes in the absence of external growth factors. Surprisingly, expression of the cyclin D1 gene, which encodes a major regulator of G1 progression, is unaltered in E7-transformed cells. In transient transfection experiments, the cyclin A gene promoter is activated by E7 via an E2F binding site. In 14/2 cells, which were used as a model system to analyze the role of HPV-16 E7 in the transformation of primary cells, we observed rapid E7-dependent activation of cyclin E gene expression, which can be uncoupled from activation of the cyclin A gene, since the latter requires additional protein synthesis. E7-driven induction of cyclin E and cyclin A gene expression was accompanied by an increase in the associated kinase activities. Two domains of the E7 oncoprotein, which are designated cd1 and cd2, are essential for transformation of rodent fibroblasts. It is shown here that growth factor-independent expression of the cyclin E gene requires cd2 but not cd1, while activation of cyclin A gene expression requires cd1 function in addition to that of cd2. These data suggest that cyclin A gene expression is controlled by two distinct negative signals, one of which also restricts expression of the cyclin E gene. The ability of E7 to separately override each of these inhibitory signals, via cd1 and cd2, cosegregates with its ability to fully transform rodent fibroblasts. Unlike serum growth factors, E7 induces S-phase entry without activating cyclin D1 gene expression, in keeping with the finding that cyclin D1 function is not required in cells transformed by DNA tumor viruses.

3T3 Cells↗

PubMedDate not supplied

Enhanced expression of cyclin E and cyclin A in human hepatocellular carcinomas.

BACKGROUND: Disruption of the G1/S check point leads to uncontrolled cell growth, resulting in the development of cancers. MATERIALS AND METHODS: Cell cycle regulatory molecules were investigated in 33 surgically resected hepatocellular carcinoma (HCC) samples from 30 patients by Western blotting. RESULTS: Enhanced expressions of cyclin E and cyclin A were detected at frequencies of 18/33 and 26/33 in HCCs, respectively, as compared with their neighboring noncancerous tissues. The enhanced expression of cyclin E, but not that of cyclin A, correlated with hyperphosphorylation of pRb and high frequency of Ki-67-positive cells. Thus, the HCCs with enhanced cyclin E expression probably contain a relatively large number of proliferating cancer cells. CONCLUSIONS: The degree of cyclin E expression can be used as a prognostic parameter of HCC. In addition, cyclin E may become a molecular target in the treatment of HCCs.

Aged↗

PubMed2002

Cyclin E and cyclin A are likely targets of Src for PDGF-induced DNA synthesis in fibroblasts.

How tyrosine kinases of the Src family regulate platelet-derived growth factor (PDGF)-induced DNA synthesis remains elusive. Here we show that the E1A antigen of adenovirus 5 overrides the G1 block elicited by the kinase-inactive mutant SrcK(-). This was dependent upon the CR2 region of E1A that upregulated cyclin E and cyclin A and inactivated the pocket protein pRb. E1A rescue was independent of pRb. Expression of SrcK(-) in fibroblasts prevented PDGF-induced expression of cyclins E and A. This effect was overcome by E1A. Constitutive expression of cyclins E and A, but not D1, restored mitogenesis that was inhibited by SrcK(-). We conclude that both cyclin E and cyclin A are likely targets of Src mediating PDGF-induced DNA synthesis.

3T3 Cells↗

PubMed2006

Parallel cyclin E and cyclin A expression in neoplastic lesions of the uterine cervix.

Cyclin E levels are high during late G1 and early S-phase in normal cells. The cyclin E expression over the cell cycle in tumours is not fully known. The impact on patient outcome by high cyclin E levels during other parts of the cell cycle than late G1- and early S-phase is unknown. We set out to study the expression of cyclin E over the cell cycle in cervical carcinomas. Using immunofluorescence staining of cyclin A, digital microscopy, and digital image analysis, we determined which cells in a tissue section that were in S- or G2-phase. M-phase cells were detected by morphology. By simultaneously staining for cyclin E, we investigated the variation in cyclin E levels over the cell cycle in cervical carcinoma lesions. In a case-control study, in which each deceased patient was matched with a patient still alive and well after >5 years of follow-up, we found that the deceased patients had a considerably higher fraction of cyclin A-positive cells staining for cyclin E than the survivors (n = 36). We conclude that parallel cyclin E and cyclin A expression is an indicator for poor outcome in cervical carcinomas. In addition, we investigated the expression pattern of cyclin E and cyclin A in consecutive biopsy samples from cervical carcinomas at different stages, as well as in human papillomavirus positive or negative adenocarcinomas in order to further study the cyclin E and cyclin A expression pattern in neoplastic lesions of the uterine cervix.

Adenocarcinoma↗

PubMed1999

Ectopic expression of Cdc25A accelerates the G(1)/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases.

Human Cdc25 phosphatases play important roles in cell cycle regulation by removing inhibitory phosphates from tyrosine and threonine residues of cyclin-dependent kinases. Three human Cdc25 isoforms, A, B, and C, have been discovered. Cdc25B and Cdc25C play crucial roles at the G(2)/M transition. In the present study, we have investigated the function of human Cdc25A phosphatase. Cell lines that express human Cdc25A in an inducible manner have been generated. Ectopic expression of Cdc25A accelerates the G(1)/S-phase transition, indicating that Cdc25A controls an event(s) that is rate limiting for entry into S phase. Furthermore, we carried out a detailed analysis of the expression and activation of human Cdc25A. Activation of endogenous Cdc25A occurs during late G(1) phase and increases in S and G(2) phases. We further demonstrate that Cdc25A is activated at the same time as cyclin E- and cyclin A-dependent kinases. In vitro, Cdc25A dephosphorylates and activates the cyclin-Cdk complexes that are active during G(1). Overexpression of Cdc25A in the inducible system, however, leads to a premature activation of both cyclin E-Cdk2 and cyclin A-Cdk2 complexes, while no effect of cyclin D-dependent kinases is observed. Furthermore, Cdc25A overexpression induces a tyrosine dephosphorylation of Cdk2. These results suggest that Cdc25A is an important regulator of the G(1)/S-phase transition and that cyclin E- and cyclin A-dependent kinases act as direct targets.

Animals↗

PubMed2003

Expression and prognostic value of the cell-cycle regulatory proteins, Rb, p16MTS1, p21WAF1, p27KIP1, cyclin E, and cyclin D2, in ovarian cancer.

To investigate the role of cell-cycle regulatory proteins in ovarian cancer, we performed immunohistochemistry for the cell-cycle promoters cyclin E and cyclin D2 and the cell-cycle inhibitors, Rb, p16MTS1, p21WAF1, and p27 KIP1, in 93 ovarian carcinomas (77 with follow-up data). The results were correlated with clinicopathological parameters and the prognostic value was determined by multivariate analysis. Strong Rb and moderate-high cyclin E immunoreactivity in carcinomas were weakly associated with high expression of the proliferation marker Ki67. By Cox's multivariate analysis, advanced stage (p=0.013), strong Rb expression (p=0.006), and negative-weak p21 staining (p=0.011) were independent prognostic indicators of short overall survival, indicating an apparently paradoxical role of the retinoblastoma protein in these tumors. In addition, trends pointing to an association of higher age (p=0.067) and positive cyclin E immunoreactivity (p=0.093) with an unfavorable prognosis were observed.

Adult↗

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↗

PubMed2001

Inhibition of cyclin E-cyclin-dependent kinase 2 complex formation and activity is associated with cell cycle arrest and withdrawal in oligodendrocyte progenitor cells.

Stimulatory and inhibitory signals regulate cell proliferation through the activity of specific enzymes that operate in distinct phases of the cell cycle. We have studied cell cycle progression, arrest, and withdrawal in the oligodendrocyte progenitor (OP) cell model system, focusing on the G(1) phase and G(1)-S transition. Not only were proliferating OPs found to display higher protein levels of cyclin E and D and cyclin-dependent kinases (cdk) 2, 4, and 6 than cells that had permanently withdrawn from the cycle, but the kinase activities of both cyclin D-cdk4/6 and cyclin E-cdk2 were also higher in dividing OPs. This was associated with a decrease in the formation of the cyclin E-cdk2 and cyclin D-cdk4/cyclin D-cdk6 complexes in differentiated oligodendrocytes that had permanently withdrawn from the cell cycle. Reversible cell cycle arrest in G(1) induced by glutamatergic and beta-adrenergic receptor activation or cell depolarization, however, did not modify cyclin E and cdk2 protein expression compared with proliferating OPs. Instead, these agents caused a selective decrease in cdk2 activity and an impairment of cyclin E-cdk2 complex formation. Although cyclin D protein levels were higher than in proliferating cells, cyclin D-associated kinase activity was not modified in G(1)-arrested OPs. Analysis in corpus callosum in vivo showed that cyclin E-cdk2 activity increased between postnatal days 3 and 15 and decreased between postnatal days 15 and 30. Our results indicate that the cyclin E-cdk2 complex is a major regulator of OP cell cycle progression and that the cdks involved in reversible cell cycle arrest are distinct from those implicated in permanent cell cycle withdrawal.

Adrenergic beta-Agonists↗

PubMed1999

Progesterone inhibits estrogen-induced cyclin D1 and cdk4 nuclear translocation, cyclin E- and cyclin A-cdk2 kinase activation, and cell proliferation in uterine epithelial cells in mice.

The response of the uterine epithelium to female sex steroid hormones provides an excellent model to study cell proliferation in vivo since both stimulation and inhibition of cell proliferation can be studied. Thus, when administered to ovariectomized adult mice 17beta-estradiol (E2) stimulates a synchronized wave of DNA synthesis and cell division in the epithelial cells, while pretreatment with progesterone (P4) completely inhibits this E2-induced cell proliferation. Using a simple method to isolate the uterine epithelium with high purity, we have shown that E2 treatment induces a relocalization of cyclin D1 and, to a lesser extent, cdk4 from the cytoplasm into the nucleus and results in the orderly activation of cyclin E- and cyclin A-cdk2 kinases and hyperphosphorylation of pRb and p107. P4 pretreatment did not alter overall levels of cyclin D1, cdk4, or cdk6 nor their associated kinase activities but instead inhibited the E2-induced nuclear localization of cyclin D1 to below the control level and, to a lesser extent, nuclear cdk4 levels, with a consequent inhibition of pRb and p107 phosphorylation. In addition, it abrogated E2-induced cyclin E-cdk2 activation by dephosphorylation of cdk2, followed by inhibition of cyclin A expression and consequently of cyclin A-cdk2 kinase activity and further inhibition of phosphorylation of pRb and p107. P4 is used therapeutically to oppose the effect of E2 during hormone replacement therapy and in the treatment of uterine adenocarcinoma. This study showing a novel mechanism of cell cycle inhibition by P4 may provide the basis for the development of new antiestrogens.

Animals↗