UNIPROT:Q06643 - FACTA Search

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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein p27KIP1 belongs to a recently identified family of proteins termed cyclin-dependent kinase inhibitors (CDKIs). These proteins play an important role in regulating cell-cycle progression and loss of their function has been implicated in tumorigenesis. Transforming growth factor beta (TGF-beta) may induce cell growth arrest through p27 activation. TGF-beta often loses its ability to arrest growth of transformed cells; this could potentially occur through a defect in p27. To determine the role of p27 in tumorigenesis, we examined its mutational status in 74 non-Hodgkin's lymphomas (NHLs) (52 of B-cell phenotype, 22 of T-cell phenotype), 5 lymphoma cell lines, and 42 adult T-cell leukemias/lymphomas (ATLs) using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and Southern blot analyses. A nonsense mutation (stop codon) that could result in expression of a truncated nonfunctional p27 protein was detected at codon 76 in one case of acute lymphomatous ATL, but not in matched normal tissues. Previously undescribed polymorphisms were also identified at codon 109 in the lymphomas and at codon 55 in the ATLs. Two homozygous deletions of the p27 gene were detected in one case of B-immunoblastic NHL and in one case of acute ATL by Southern blot hybridization. These results indicate that p27 gene alterations are rare events in NHLs and ATLs, but may play an important role in the pathogenesis of some hematologic malignancies.
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PMID:Alterations of the p27KIP1 gene in non-Hodgkin's lymphomas and adult T-cell leukemia/lymphoma. 765 21

Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16CDKN2 and p15CDKN2B have been described in B cell non-Hodgkin's lymphoma (B-NHL). We describe a new B-NHL cell line (Granta 519), with concurrent abnormalities of the cyclin D1, pl6CDKN2 and pl5CDKN2B genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16CDKN2 gene was also identified, suggesting that this combination of oncogenic aberration is a pathophysiologic contribution to a subset of NHL cases. More in-depth functional studies of this concept were facilitated by the availability of the cell line Granta 519 which was derived from a case of high-grade NHL and has a mature B cell immunophenotype. Cytogenetic analysis identified translocation t(11;14)(q13;q32) and complex rearrangements involving chromosomes 9p22, 13p21, 17pl1, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16CDKN2 and p15CDKN2B genes. To elucidate the effect of these genetic abnormalities on the G1 control of Granta 519 cells, the level and function of the major components of the cyclinD/retinoblastoma (RB) pathway were investigated. Cyclin D1 was dominant among the D-type cyclins, formed abundant complexes with cyclin-dependent kinase (Cdk) Cdk4 rather than Cdk6, and the immunoprecipitated cyclin D1/Cdk4 holoenzyme was active as a pRB kinase. Electroporation of wild-type pl6CDKN2 arrested the Granta 519 cells in G1, consistent with the p16CDKN2 loss as a biologically relevant event during multistep evolution of the tumor, and with the expression of functional pRB. Direct cooperation of these distinct abnormalities to cell-cycle, deregulation in NHL cells was suggested by G1 acceleration upon inducible overexpression of cyclin D1 in a control breast cancer cell line lacking p16CDKN2, an effect which could be prevented by ectopic expression of p16CDKN2. Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor. Further clinicopathologic studies of this possibility are warranted.
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PMID:Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin's lymphomas. Functional studies in a cell line (Granta 519). 900 20

Inactivation of the cyclin-dependent kinase inhibitors p16INK4A and p15INK4B are frequent alterations in neoplasia, often resulting from homozygous deletion or promoter region hypermethylation. We have analyzed both modes of inactivation of p15INK4B and p16INK4A in the major types of adult and pediatric hematological malignancies. Hypermethylation of p15INK4B, without alteration of p16INK4A, was an almost universal finding in adult acute myelogenous leukemia, and occurred very frequently in adult acute lymphocytic leukemia and pediatric acute myelogenous leukemia and acute lymphocytic leukemia. In contrast, neither p15INK4B nor p16INK4A were inactivated in any stage of chronic myelogenous leukemia. Hypermethylation of p16INK4A, often without alterations of p15INK4B, was found in non-Hodgkin's lymphoma and was much more frequent in cases with high-grade than low-grade histology. Enriched normal bone marrow stem cells had no detectable promoter region methylation of these genes, as analyzed by a newly developed PCR method. Remarkably distinct patterns of inactivation of p15INK4B and p16INK4A characterize different types of hematological malignancy, and alterations in these tumor suppressor genes are one of the most common alterations in hematological malignancies.
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PMID:Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. 904 Nov 82

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

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.
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PMID:Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor. 966 78

In order to survive, cells need tight control of cell cycle progression. The control mechanisms are often lost in human cancer cells. The cell cycle is driven forward by cyclin-dependent kinases (CDKs). The CDK inhibitors (CKIs) are important regulators of the CDKs. As the name implies, CKIs were initially shown to negatively regulate CDK activity. However, recent data indicates that the members of the Kip/Cip family of CKIs, including p27, exert both positive and negative regulation of CDK activity at the G1/S phase transition. Mutations of Kip/Cip genes are rare, but p27 knockout mice are tumor prone when challenged with carcinogenic stimuli. Numerous studies of various human non-hematological tumors have identified low expression of p27 as a predictor of poor prognosis. In non-Hodgkin's lymphoma (NHL), we and others have also shown the independent prognostic value of p27 expression. In distinct NHL entities however, shortened survival seems to correlate with high expression of p27. For definitive assessment of the role played by p27 in lymphomagenesis, and the prognostic value of p27 in these tumors, further studies of distinct NHL entities are needed. This review addresses the function of p27 and the other Kip/Cip proteins in G1/S phase transition and their possible role in tumorigenesis with emphasis on p27 and NHL.
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PMID:P27 in cell cycle control and cancer. 1097 80

This review focuses on the clinical development of the prototype broad spectrum inhibitor of cyclin-dependent kinases (CDKs), flavopiridol, now undergoing Phase II single-agent trials and Phase I combination trials (with paclitaxel and cisplatin). Preclinically, flavopiridol is a potent inhibitor of CDKs 1, 2 and 4 in cell-free assays (IC(50)in the region of 100 nM) and tumour cell growth in vitro (typical IC(50)in the region of 100 nM). The drug showed in vivo antitumour activity (using iv., ip. or oral dosing) against a variety of human tumour xenografts, especially when administered on a regular daily, rather than weekly, schedule and most notably against prostate carcinoma, head and neck cancer, non-Hodgkin's lymphoma and leukaemia. The major toxicities observed in rodents were on the bone marrow and gastrointestinal tract. Pharmacokinetics were linear with dose and with a bi-exponential decline both in rodents and man. Oral bioavailability in rodents is in the region of 20%. Glucuronidation appears to be the major route of metabolism. Single-agent clinical trials have mainly used a 72 h continuous infusion schedule. Dose-limiting toxicities were diarrhoea and hypotension. Plasma concentrations in excess of those required for in vitro enzyme or cell growth inhibition are achievable. While there has been some evidence of single-agent antitumour activity (partial responses in a patient with renal cancer and another with gastric cancer), ongoing combination studies, especially with paclitaxel, where preclinical synergistic antitumour effects are observed, are promising. Doubt as to whether CDKs are the sole target responsible for the drug's antitumour effects have been raised by preclinical observations of apoptosis of non-cycling cells, effects on endothelial cells and non-CDK proteins, such as aldehyde dehydrogenase and glycogen phosphorylase, potent effects on PTEFb and transcription and its ability to directly interact with DNA.
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PMID:Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. 1109 60

Different studies have already shown that the isolated inactivation of p21, p16, or p27 cyclin-dependent kinase inhibitors (CKIs) is associated with increased growth fraction, tumor progression, or decreased overall survival in cases of non-Hodgkin's lymphoma. In this study we linked molecular study of the p53 and p16 genes with immunohistochemical analysis of p27 expression in a group of aggressive B-cell lymphomas [large B-cell lymphomas (LBCLs) and Burkitt's lymphomas]. This was done to analyze the relationship between p53 and p16 silencing, p27 anomalous overexpression, and clinical follow-up, testing the hypothesis that the accumulation of CKI alterations could confer to the tumors a higher aggressivity. In a group of 62 patients, p53 inactivation as a result of mutation was observed in 11 cases (18%) and p16 silencing was seen in 27 cases (43.5%) as a result of methylation (20 of 62), 9p21 deletion (7 of 44), or p16 mutation (2 of 62). The simultaneous inactivation of p53 and p16 was detected exclusively in five LBCL cases. Anomalous expression of p27, which has been proven to be associated with the absence of p27/CDK2 complexes and the formation of p27/cyclin D3 complexes where p27 is inactivated, was detected in 19 of 61 cases (31%). Cases characterized by p27 anomalous expression display concurrent inactivation of p21 (provided by p53 mutations) and/or p16 CKIs in 11 of 14 LBCL cases (P = 0.040). When the relationship between the association of inactivated CKIs and overall survival was considered, a significant relationship was found between a lower overall survival probability and an increased number of inactivated CKIs in LBCL cases, with the worst prognosis for the cases displaying concurrent p53, p16, and p27 alterations. This proves that simultaneous inactivation of different tumor suppressor pathways does indeed take place, and that tumor aggressiveness takes advantage of this CKI-concerted silencing. In this same series of data, Burkitt's lymphoma patients seem to behave in a different way than LBCLs, with p53 and p16 alteration being mutually exclusive and the association with p27 anomalous expression not being clinically significant. These facts seem to support that the additive effect of the inactivation of different CKIs could be dependent of the histological type.
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PMID:Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. 1143 67

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.
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PMID:Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. 1281 36

The p16 (CDKN2a/INK4a) gene is an important tumor-suppressor gene, involved in the p16/cyclin-dependent kinase/retinoblastoma gene pathway of cell cycle control. The p16 protein is considered to be a negative regulator of the pathway. Promoter hypermethylation resulting in inactivation of the p16 gene has been found in various hematopoietic malignancies, including non-Hodgkin's lymphoma, and may play a role in transformation/clinical aggressiveness of those tumors. However, the p16 protein expression in primary gastric lymphoma has not been studied. In this study, we characterize protein expression and promoter hypermethylation of the p16 gene in B-cell primary gastric lymphomas from China. In all, 43 cases of B-cell primary gastric lymphoma were investigated. They consisted of 24 (56%) cases of diffuse large-cell lymphoma, 12 (28%) cases of extranodal marginal zone lymphoma, six (14%) cases of extranodal marginal zone lymphoma with large-cell transformation and one (2%) case of follicular lymphoma. Loss of p16 protein expression was found in 34 (79%) out of 43 cases, while the remaining nine (21%) cases showed positivities for the p16 protein. All 43 cases were further characterized by methylation-specific polymerase chain reaction (PCR) to analyze p16 promoter hypermethylation status. In total, 11 (26%) of 43 cases were positive for p16 promoter hypermethylation. Among those, 10 (30%) out of the 33 cases negative for the p16 immunostaining showed promoter hypermethylation, whereas only one (10%) out of the 10 cases that were positive for the p16 immunostaining displayed promoter hypermethylation. Of the 43 cases, 30 had limited pathologic data at the time of resection. Primary gastric lymphoma involved extragastric sites (lymph node or liver) in 17 (57%) of 30 cases, while the remaining 13 (43%) cases were only limited to the stomach. Loss of p16 protein expression was found in 14 (82%) of 17 cases with extragastric involvement and in 11 (85%) of 13 cases without such involvement. In conclusion, loss of p16 protein expression is frequent in those B-cell primary gastric lymphomas and approximately one-third of such loss correlated with promoter hypermethylation. Despite limited pathologic data, loss of p16 protein expression appears not to be correlated with extragastric involvements.
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PMID:Promoter hypermethylation and protein expression of the p16 gene: analysis of 43 cases of B-cell primary gastric lymphomas from China. 1497 29

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