Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p21WAF1/CIP1 is a nuclear protein that binds to cyclin-dependent kinase complexes (CDKs) and inhibits the activity of multiple kinases. These CDKs are involved in the regulation of cell cycle progression at several checkpoints. In this study, the authors have analyzed by immunohistochemistry the expression of p21WAF1/CIP1 in normal uterine tissues, 12 endometrial hyperplasias, 17 endocervical adenocarcinomas, and 31 endometrial adenocarcinomas. In addition, a group of 10 leiomyomas and 10 uterine leiomyosarcomas were also stained. To evaluate cell proliferation, the monoclonal antibody Ki-67 was used in all of the available cases. Terminally differentiated epithelial endocervical and endometrial cells showed variable expression of p21WAF1/CIP1, whereas the endometrial hyperplasias, and endocervical and endometrial adenocarcinomas showed decreased expression or were negative. All of the cases of cervical squamous dysplasia were positive. Normal smooth muscle cells and 50% of leiomyomas were negative, whereas all leiomyosarcomas showed expression of p21WAF1/CIP1. These results indicate that p21WAF1/CIP1 contributes to differentiation in normal endometrial and endocervical glands. The decreased expression of p21WAF1/CIP1 in endometrial hyperplasias and carcinomas may be important in the process of neoplastic transformation. The role of certain CDK inhibitors, such as p21WAF1/CIP1, is different in epithelial and mesenchymal tumorigenesis in the uterus.
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PMID:Immunohistochemical localization of p21(WAF1/CIP1) in normal, hyperplastic, and neoplastic uterine tissues. 901 33

The response to therapy of leukemic cells is largely determined by their capacity of proliferation and apoptosis in presence of the administered drugs. We describe here the main markers used in flow cytometry (FCM) and involved in the assessment of cell cycle parameters: single labeling by Propidium Iodide (PI) and double labeling anti-Bromodeoxyuridine (BrdUrd)/PI which, both in vitro and in vivo, gives cell percentages in the different cell cycle phases. The markers of cell cycle progression can be divided into proliferation markers such as PCNA (proliferating cell nuclear antigen) or Ki-67 and cell cycle progression markers. The latter, which are the core of the cell cycle machinery, are molecules recently characterized (Cyclins, CDKs (cell dependent kinases), CDIs (cyclin-dependent kinase inhibitors)) and their cell expression can be analyzed using FCM. FCM is also one of the best means to detect and quantitate apoptotic cells. Several techniques are described: Nuclear labeling using Hoechst 33342: mitochondrial labeling using DiOC6(3): detection of DNA fragmentation using 1) labeling of fixed and permeabilized cells with a DNA marker or 2) labeling of the free 3' DNA ends using incorporation of labeled deoxynucleotides; detection in apoptotic cells (Bcl-2, Fas, phospholipids...). At last, we analyzed flow cytometry methods to study the cell resistance to Ara-C and anthracyclins. In combination with cell kinetic studies and detection of apoptotic cells, they should increase the efficiency of the acute leukemia treatment.
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PMID:Flow cytometry study of cell cycle, apoptosis and drug resistance in acute leukemia. 903 Sep 62

The p27kip1 (p27) gene encodes an inhibitor of cyclin-dependent kinase activity. The expression of p27 protein in normal and neoplastic tissues was investigated by immunoblotting and immunohistochemistry. Immunoblotting studies detected a 27-kd protein band that was decreased in neoplastic pituitary tissues compared with normal pituitary. Immunostaining of 177 tissues showed abundant expression of p27 protein in normal tissues with decreased numbers of immunoreactive cells in adenomas and carcinomas in both endocrine and nonendocrine tissues. p27 expression was inversely related to the proliferation marker Ki-67 antigen detected with monoclonal antibody MIB-1. Parathyroid adenomas and hyperplasias had similar Ki-67 labeling indices; however, hyperplasias had threefold more p27-positive cells than parathyroid adenomas, suggesting that p27 immunostaining may be useful in distinguishing between these two conditions. These results indicate that there is widespread aberrant p27 expression in hyperplastic tissues and in benign and malignant neoplasms compared with normal tissues. Immunohistochemical analysis of p27 along with Ki-67 may be used to assess the biological behavior of various neoplasms, to classify hyperplastic and neoplastic tissues, and to study cell cycle regulation during tumor progression.
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PMID:Aberrant p27kip1 expression in endocrine and other tumors. 903 55

Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CDKIs). p27KIP1, which has a high degree of similarity with p21WAF1, is a general CDKI thought to be involved in G1 arrest in response to agents that inhibit cell cycle progression. The aims of this study were 1) to establish the pattern of expression of p27KIP1 protein in nontumor lymphoid tissue, 2) to determine whether p27KIP1 is involved in lymphomagenesis, and 3) to address the possible relationship between p27KIP1 and p21WAF1 expression in reactive and tumor lymphoid tissue. p27KIP1 protein was found to be mainly present in quiescent lymphocytes in reactive lymphoid tissue as well as in peripheral blood lymphocytes, with an inverse expression for p27KIP1 and Ki-67 proteins. The same p27KIP1 expression pattern was observed in lymphomas, independently of histological type; small resting cells were p27KIP1 positive, and large proliferating cells were p27KIP1 negative. Therefore, tumors with a low proliferative index were mostly positive, whereas tumors characterized by a higher growth fraction bad low p27KIP1 protein levels. An unexpected finding was the existence of a group of six cases of high-grade lymphomas (three diffuse large B-cell lymphomas and three Burkitt's lymphomas) with homogeneously strong staining for p27KIP1 protein. All 6 of these cases belong to a group of 28 cases characterized by blockage of the p53 tumor suppressor pathway, as determined by genetic (p53 mutation) or immunophenotypic studies (p53+/p21-). p27KIP1 expression was not seen in any case of aggressive non-Hodgkin's lymphoma with an intact p53 pathway. The results indicate that p27KIP1 is down-regulated in lymphomas with a high proliferative index, although it is highly expressed in high-grade lymphomas with defects in the p53 pathway.
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PMID:Cyclin-dependent kinase inhibitor p27KIP1 in lymphoid tissue: p27KIP1 expression is inversely proportional to the proliferative index. 921 41

Breast cancer is a heterogeneous disease regarding morphology, invasive behavior, metastatic capacity, hormone receptor expression and clinical outcome. For prediction of prognosis, tumor cell kinetics is an important feature, traditionally evaluated by estimation of cell growth-associated parameters such as mitotic index, S-phase fraction and expression of proliferation coupled proteins, for example proliferating cell nuclear antigen (PCNA) and Ki-67 antigen. Recent data indicate that deregulation of the cell cycle can occur at different levels in cancer and that the "deregulation pattern" can be of clinical significance. In the present overview we give a short description of approaches used for cell proliferation assessments, whereafter more recent data on cell cycle deregulation are discussed. Alterations of importance in breast cancer include overexpression of cyclins D1 and E, down-regulation of cyclin-dependent kinase inhibitors, such as p16, and inactivation of the retinoblastoma and p53 tumor suppressor proteins.
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PMID:The cell cycle in breast cancer. 929 94

Genetic alterations in the p53 tumor suppressor gene are common in human colorectal cancers, occurring in approximately 70% of tumors. In vitro studies have shown that wild-type p53 is involved in controlling cell cycle checkpoint functions and apoptosis involved in the cytotoxic response induced by ionizing radiation and several anticancer chemotherapeutic agents. Wild-type p53 protein can transcriptionally activate the WAF gene, which encodes a cyclin-dependent kinase inhibitory protein, p21WAF1/C1PI protein, and transcriptionally repress the bcl-2 gene, which encodes an inhibitor of apoptosis. To learn more about the in vivo relationship between p53 protein and the expression of p21WAF1/C1PI and bcl-2 proteins in human colorectal cancers treated with radiation therapy, we examined the expression of these proteins by immunohistochemistry in pre-irradiated biopsy specimens and surgical specimens with residual tumor of 27 patients with colorectal carcinoma. Cell proliferation was measured using Ki-67 expression in the tumor cells. The p53 protein was not detected in normal colorectal mucosa, but it was expressed in 21 of 27 (78%) of pre-irradiated tumor samples and in 19 of 27 (70%) of post-irradiated tumors. Expression of the bcl-2 protein in normal colorectal mucosa was confined to the basal epithelial cells of the crypts. Diffuse bcl-2 staining was detected in tumor cells in 13 of 27 (48%) of pre-irradiated samples and in 14 of 27 (52%) of post-irradiated samples. p21WAF1/C1PI expression was detected in 14 of 27 (52%) of pre-irradiated samples but only in 7 of 27 (26%) of post-irradiated samples. No inverse relationship between expression of p53 protein and abnormal bcl-2 expression was apparent. p21WAF1/C1PI was expressed in most nonproliferating Ki-67-negative epithelial cells at the apical tips of the crypts in normal colorectal mucosa, but not in proliferating Ki-67-positive cells of adjacent adenomatous mucosa. An inverse relationship between Ki-67 and p21WAF1/C1PI expression was observed in normal colorectal mucosa and adjacent adenomatous mucosa. After radiation therapy, p53 protein accumulation did not change among residual tumors in 18 cases (three of which were initially negative and remained negative); in four cases there was a significant increase, and five cases had a substantial decrease of p53 expression. Aberrant bcl-2 expression is not correlated with expression of p53 and does not increase significantly in post-irradiated tumor cells. p21WAF1/C1PI expression is markedly reduced in tumor cells that survive radiation therapy.
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PMID:The role of p53, p21WAF1/C1PI, and bcl-2 in radioresistant colorectal carcinoma. 934 26

Recent studies have shown that the cyclin-dependent kinase (cdk) inhibitors play important roles in cell cycle progression in normal cells. Alterations in the cdk inhibitors also appear to be important in cancer development in a number of human tumors. p27Kip1 is a member of the CIP/KIP family of cdk inhibitors that negatively regulates cyclin-cdk complexes. Reduced levels of p27Kip1 protein have been identified in a number of human cancers, and in some cases reduced p27Kip1 is associated with an increase in proliferative fraction. In the present study, we examined p27Kip1 protein by immunohistochemistry in 10 normal and 36 dysplastic epithelia and in 8 squamous cell carcinomas from one anatomical site within the oral cavity, the floor of the mouth. Proliferative activity was assessed in serial sections by determining the expression of the cell cycle proteins Ki-67 and cyclin A. p27kip1 protein was significantly reduced in oral dysplasias and carcinomas compared with that in normal epithelial controls. In addition, there was a significant reduction in p27Kip1 protein between low- and high-grade dysplasias, suggesting that changes in p27Kip1 expression may be an early event in oral carcinogenesis. There was increasing expression of Ki-67 and cyclin A proteins with increasingly severe grades of dysplasia compared with normal controls. Although there was a strong correlation between Ki-67 and cyclin A scores (r2= 0.61) for all categories of disease, there was a weak negative correlation between Ki-67 and p27Kip1 levels (r2 = 0.29) and between cyclin A and p27Kip1 levels (r2 = 0.25). In conclusion, this study has found that a reduction in the proportion of cells expressing p27Kip1 protein is frequently associated with oral dysplasia and carcinoma from the floor of the mouth. Furthermore, reductions in p27Kip1 levels are associated with increased cell proliferation, although other changes likely contribute to altered cell kinetics during carcinogenesis at this site.
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PMID:Reduced levels of the cell-cycle inhibitor p27Kip1 in epithelial dysplasia and carcinoma of the oral cavity. 946 85

Recent evidence has implicated cyclins and cyclin-dependent kinases in the evolution and progression of various malignancies. We studied the immunohistochemical expression of cyclin A, cyclin B, and cyclin-dependent kinase p34cdc2 in a broad spectrum of benign and malignant melanocytic lesions. Formalin-embedded, parrafin-fixed tissue sections from 66 malignant melanomas (MM) and 60 benign nevi were examined for the expression of these cell-cycle proteins. The results were compared with the standard proliferative marker Ki-67 and mitotic index. MM showed significantly higher immunoreactivity for cyclin A, cyclin B, p34cdc2, and Ki-67 compared with benign nevi. Cyclin A, p34cdc2, and Ki-67 displayed strong co-expression in MM. Overexpression of cyclin A and p34cdc2 correlated with histological type, mitotic activity, Ki-67 index, tumor thickness, Clark's level, and clinical outcome in MM. In invasive MM, increased immunostaining of cyclin A and Ki-67 were associated with decreased patient survival. These findings indicate potential roles of mitotic cyclins and cyclin-dependent kinases in the pathogenesis and progression of malignant melanoma.
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PMID:Mitotic cyclins and cyclin-dependent kinases in melanocytic lesions. 978 46

A cyclin-dependent kinase (cdk) inhibitor, p27Kip1 (p27), binds to the cyclin E-cdk2 complex and functions as a suppressor of cell cycle promotion. Here, the involvement of p27 in the growth of normal human endometrium was immunohistochemically studied, and the findings were compared with those of Ki-67, cyclin E and cdk2. In addition, to elucidate the effect of progesterone on the expression of p27, tissues from patients with endometrial hyperplasia were examined before and after the administration of medroxyprogesterone acetate (MPA) for the treatment of this disease. In the glandular cells of the normal endometrium, p27 was negligible during the proliferative phase, whereas it was markedly increased in the secretory phase. The staining pattern of Ki-67 was the reverse. Cyclin E/cdk2-positive cells were observed throughout the menstrual cycle. In the secretory phase, the cyclin E/cdk2-positive cells were also positive for p27, suggesting an interaction between these molecules. Stromal cells, especially in the basalis, showed a consistent expression of p27 throughout the menstrual cycle. The expression of p27 in hyperplastic epithelia before the MPA treatment was negligible, whereas it was greatly increased after the treatment. The Ki-67 positivity decreased after the treatment. These findings suggest that p27 is involved in the progesterone-induced growth suppression of normal and hyperplastic endometria.
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PMID:Involvement of cyclin-dependent kinase inhibitor p27Kip1 in growth inhibition of endometrium in the secretory phase and of hyperplastic endometrium treated with progesterone. 978 52

Mature podocytes are regarded as growth-arrested cells with characteristic phenotypic features that underlie their function. To determine the relationship between cell cycle regulation and differentiation, the spatiotemporal expression of cyclin A, cyclin B1, cyclin D1, the cyclin-dependent kinase inhibitors (CKIs) p27 and p57, and markers of differentiating podocytes in developing human kidneys was investigated by immunohistochemistry. In S-shaped body stage, Ki-67, a cell proliferation marker that labels the G1/S/G2/M phase, was expressed in the majority (more than 80%) of presumptive podocytes, along with cyclin A (approximately 20% of the Ki-67-positive cells) and cyclin B1 (less than 5% of Ki-67-positive cells) expression. Among these cells), cyclin D1 and CKIs were markedly down-regulated. At the capillary-loop stage, by contrast, CKIs and cyclin D1 were intensely positive in podocytes, whereas no Ki-67, cyclin B1, or cyclin A expression was seen. Moreover, double-immunolabeling and serial-section analysis provided evidence that CKIs and markers specific for differentiating podocytes, namely PHM-5 (podocalyxin-like protein in humans), synaptopodin (a foot process-related protein), and C3b receptor, were co-expressed at the capillary-loop stage. Podocytes were the only cells within the glomeruli that expressed CKIs at immunohistochemically detectable levels. Furthermore, bcl-2 (an apoptosis inhibitory protein) showed a reciprocal expression pattern to that of CKI. These results suggest that 1) the cell cycle of podocytes is regulated by cyclin and CKIs, 2) CKIs may act to arrest the cell cycle in podocytes at the capillary-loop stage, and 3) the specific cell cycle system in podocytes may be closely correlated with their terminal differentiation in humans.
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PMID:Cell cycle regulation and differentiation in the human podocyte lineage. 981 43


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