Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinase inhibitors (CDKIs) can be classified into two groups based on the structure of the proteins. One group includes the p21 (CIP1, WAF1, CAP20), p27 (Kip1), and p57 (Kip2) CDKIs, which contain a homologous amino-terminal cyclin-dependent kinase (cdk) inhibitory domain. The p16 (INK4A), p15 (INK4B), and p18 (INK4C) CDKIs, which have an ankyrin repeat motifs, belong to the other group. The p16 and p15 CDKI genes are very frequently altered in a variety of cancers including hematopoietic malignancies. The p19 (INK4D) gene is a newly cloned CDKI which belongs to the latter group. To determine if p19 genetic alterations play a role in hematopoietic malignancies, we examined DNA from 45 childhood newly diagnosed acute lymphocytic leukemias (ALLs), 30 acute myeloblastic leukemias (AMLs), 10 chronic myelocytic leukemias (CMLs), 45 adult T cell leukemias (ATLs), 70 non-Hodgkin's lymphomas (NHLs), and 20 multiple myelomas (MM) as well as 14 ALL, 20 AML, two ATL, and five lymphoma cell lines. Using Southern blot analysis, one homozygous deletion of the p19 gene was detected in a human immunodeficiency virus (HIV)-related Burkitt-like lymphoma sample. No point mutations in any of the samples were found by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Our investigation suggests that alterations of p19 do not play an important role in the development of most hematopoietic malignancies.
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PMID:Alterations of the cyclin-dependent kinase inhibitor p19 (INK4D) is rare in hematopoietic malignancies. 894 28

p53 is a tumour suppressor gene which is often found to be inactivated in most types of human cancer. p53 is a transcription factor, the inactivation of which may lead to significant variations in the levels of p53 downstream proteins, such as p21WAF1/CIP1 and MDM2. In view of the significance of p21WAF1/CIP1 and MDM2 as wild-type (wt) p53 targets, this study was undertaken to monitor the varying expression of these proteins in non-Hodgkin's lymphomas (NHLs) in relation to p53 gene status. A total of 57 cases of different histological types of NHL were included in this study. Proteins p53, p21WAF1/CIP1, and MDM2 were analysed by immunohistochemical techniques, taking the levels expressed in reactive lymphoid tissues as reference points. p53 gene point mutations (exons 5-8) were looked for using the PCR-SSCP technique and direct sequencing. Fifteen of the 57 cases studied showed 16 mutations at the p53 gene: 12 missense, one nonsense, two silent mutations, and one frameshift deletion. Most missense mutations were associated with high levels of p53 protein, while the nonsense mutations and frameshift deletion did not induce detectable levels of p53. All cases with mutation at the p53 gene (15) showed null or low levels of p21WAF1/CIP1 and MDM2 proteins, suggesting that null or missense mutations at this gene give rise to a protein that is unable to transactivate the p21WAF1/CIP1 and MDM2 genes. The association between missense p53 mutation and dissociate immunophenotype (p53+, MDM2-, p21-) was statistically significant (Fisher's exact test, P = 0.0024). This anomalous p53+, MDM2-, p21- phenotype was also found in a small group of five cases with wt p53; this could indicate that in these cases p53 transactivation capacity has been abrogated by a mechanism other than p53 mutation. Most cases with the wt p53 gene show simultaneous immunohistochemical expression of all three proteins and often display higher levels than those found in reactive lymphoid tissue. There is a tendency for EBV-positive cases to harbour high levels of p53+ and p21+, suggesting that EBV could be involved in the nuclear accumulation of p53 and p21WAF1/CIP1 in NHL.
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PMID:p21WAF1/CIP1 and MDM2 expression in non-Hodgkin's lymphoma and their relationship to p53 status: a p53+, MDM2-, p21-immunophenotype associated with missense p53 mutations. 907 3

A large fraction of non-Hodgkin's lymphomas (NHLs) accumulate a wild-type form of the p53 tumor suppressor protein at the nuclear level. In normal cells, p53 induction is associated with a temporary cell growth arrest at the G1-S boundary of the cell cycle. This activity of p53 as a G1 checkpoint molecule is strictly dependent on its ability to induce the transcription of the inhibitor of the cyclin dependent kinase, p21. To verify the functionality of the wild-type p53 protein accumulated in NHL cells, 70 cases were comparatively analyzed for p53 and p21 expression and status of the respective genes. Overexpression of the wt p53 protein was associated with the accumulation of p21, indicating that p53 is functional with respect to p21 induction in these tumors. The coaccumulation of p53 with Ki-67 antigen indicates that wt p53-positive cells and p21-positive cells, as well, are actively proliferative elements, supporting the notion that p53-induced, p21-mediated growth arrest is somehow overridden in NHL cells. No p21 mutation or particular allele variant was shown to correlate with p21 protein accumulation, thus excluding a role for p21 structural abnormalities. Taken together, our data suggest the existence in NHL of a peculiar mechanism of functional inactivation of the p53 G1 checkpoint pathway occurring downstream of the CDK inhibitor p21.
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PMID:Human non-Hodgkin's lymphomas overexpress a wild-type form of p53 which is a functional transcriptional activator of the cyclin-dependent kinase inhibitor p21. 911 98

About one fourth of patients with Hodgkin's disease relapse after therapy. The mechanisms that lead to resistance to treatment in these patients are poorly understood. The authors describe the differential protein expression of p53, proliferating cell nuclear antigen (PCNA), and p21 at initial presentation and relapse, and discuss their role in disease progression and resistance to therapy. Thirty-four patients with Hodgkin's disease who had relapsed after standard chemotherapy and radiotherapy regimens were assessed for the expression of p53 protein, PCNA, and p21 protein (waf/cip 1). In 14 of these cases, sequential biopsies performed both at presentation and at relapse were available for the study. Seventy-five percent of the cases were positive for the p53 protein. Tumors at relapse had higher p53 and PCNA scores than those at initial presentation. In the paired samples, a significant increase was noted in the number of p53 and PCNA-positive cells and in the intensity of staining with p53 antibody. Six of seven paired samples tested for p21 showed an increased p21 expression at relapse. These results suggest that, at relapse, Reed-Sternberg (RS) cells and their variants positive for p53, PCNA, and p21 are increased in number and individually have an increased expression of p53, PCNA, and p21 proteins. These findings suggest that therapy failure and relapse may, at least in part, be associated with altered p53, p21, and PCNA pathways. HUM PATHOL 28:549-555. This work was carried out during an exchange fellowship program at the National Cancer Institute, Bethesda. There are no restrictions on its use
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PMID:A study of p53 protein, proliferating cell nuclear antigen, and p21 in Hodgkin's disease at presentation and relapse. 915 3

This study attempts to define more clearly the morphology and ultrastructure of mummified Hodgkin cells, to determine their incidence in the different histological subtypes of Hodgkin's disease (HD), and to correlate these data with the expression of p53, bcl-2, mdm2, and p21/WAF1. Forty-five cases of primary HD were examined at light and electron microscopic level. DNA strand breaks were detected by the in situ end-labelling (ISEL) and the TdT-mediated dUTP-digoxigenin nick end-labelling (TUNEL) technique. Mummified Hodgkin cells display morphological features that differ from those of classical apoptosis. In contrast to apoptotic cells, mummified Hodgkin and Reed-Sternberg (HRS) cells do not react in the ISEL or TUNEL procedures and maintain the expression of antigens such as CD30 and CD15. The morphology of mummified tissue cells could be simulated by CD95-mediated induction of apoptosis in the Hodgkin cell line HDLM2 if internucleosomal DNA fragmentation was inhibited by zinc ions. The highest incidence of mummified cells was found in the nodular sclerosis and mixed cellularity subtypes, whereas the lowest frequency was observed in nodular paragranuloma. The frequency was independent of p53, bcl-2, p21, and mdm2 expression. p21 and mdm2 immunoreactivity of HRS cells was correlated with p53 status. HRS cells in nodular paragranuloma were virtually negative for p21/WAF1 or bcl-2. Classical apoptotic cells reacting in the TUNEL and ISEL procedures are found in all subtypes of HD and are derived from the non-neoplastic cellular background. In conclusion, mummified Hodgkin cells display features of apoptosis lacking the internucleosomal DNA fragmentation. The pattern of the p53-transactivated genes mdm2 and p21/WAF1 suggests that inactivating mutations of p53 are rare in HD.
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PMID:The mummified Hodgkin cell: cell death in Hodgkin's disease. 934 31

p21 Is involved in the control of the mammalian cell cycle through the binding and inhibition of cyclin-dependent kinases. The cyclins are dependent on the phases of the cell cycle, and divided into two classes: mitotic cyclins (A, B1, B2) and G1 cyclins (C, D1, D2, D3, E). The product of the p21 gene is a potent downstream effector of the p53 tumor-suppressor gene function. The Hodgkin and Reed- Sternberg (H & RS) cells in Hodgkin's disease are reported to frequently express p53, p21, and nuclear proliferative activity (Ki-67). To clarify the relationship of p21, p53 and cyclins, we performed the immunohistochemistry of p53, p21, Ki-67, cyclin D1, cyclin E, cyclin A and cyclin B1, using 11 cases with Hodgkin's disease. In addition, we performed p53 gene sequencing of exon 5-8, and in situ hybridization of Epstein-Barr virus (EBV) EBER-1 region, whose products have reported to induce the expression of cyclin D. In this study, in all cases, Ki-67 was expressed in almost all H & RS cells, and p53 and p21 were expressed in H & RS cells. No p53 gene mutations were detected in any case, and p53 protein overexpression did not correlate with p53 gene mutations. The number of p21-positive H & RS cells was significantly related with that of the p53-positive cells. The cyclins E, A, B1 and D1 were also expressed in H & RS cells. Unexpectedly, the expression of the cyclins was not suppressed by p21 and p53 expression. In addition, the existence of EBV was not related to the expression of cyclins. It is considered that H & RS cells are, indeed, in cell cycle and commonly express the cell cyclins, and that the cell cycle of H & RS cells may not be specifically fixed in the G1, S, G2 or M phases.
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PMID:Expressions of cyclin E, A, and B1 in Hodgkin and Reed-Sternberg cells: not suppressed by cyclin-dependent kinase inhibitor p21 expression. 1046 93

Since the prevention of apoptosis can produce resistance to chemotherapy, abnormal expression of oncoproteins engaged in the regulation of this phenomenon in tumor cells may give some prognostic information in patients with neoplasma. To assess this problem in Hodgkin's disease (HD), the cellular expression of two p53 downstreams proteins p21 and MDM-2 was evaluated in the lymph nodes specimens obtained from 68 patients at the time of diagnosis, and compared with some clinical and pathological data. Positive immunoreaction for p21 and MDM-2 on Reed-Sternberg/Hodgkin's (R-S/H) cells was found in a majority of cases (58.8 and 63.2%, respectively). High expression of p21 protein correlated with poor response to the first-line treatment and disease free survival in both univariate and multivariate regression analysis, whereas expression of MDM-2 did not give prognostic information in patients with HD. Expression of p21 and MDM-2 was also compared with p53 protein immunoreactivity of R-S/H cells. The p21+/p53+ immunophenotype occurred to give particularly negative prognostic information in patients with HD. Diversity of p21/MDM-2/p53 patterns of R-S/H cells observed in particular patients may reflect heterogeneity of apoptosis regulatory mechanisms, as well as differences in p53 gene status.
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PMID:Expression of p21 and MDM-2 proteins on tumor cells in responding and non-responding patients with Hodgkin's disease. 1061

The aim was to investigate the combined immunoexpression of p53, p21, bcl-2, bax, Rb and Ki67 proteins in Hodgkin's lymphomas (HL) and correlate expression patterns with the histotype and the Epstein-Barr Virus (EBV) status. Paraffin-sections from 56 cases of HL (18 nodular sclerosis and 38 mixed cellularity) and from ten "reactive" lymph nodes were investigated. P53, p21, bcl-2, bax, Rb and Ki67 proteins were detected in Hodgkin and Reed-Sternberg (HRS) cells in 35/56, 56/56, 24/56, 23/56, 56/56 and 56/56 cases of HL, respectively. No correlation was found between the expression of each protein and the EBV status or the histotype of HL. Comparison between p53 and p21 staining revealed two patterns: a) p53+/p21+ (35 cases); and b) p53-/p21+ (21 cases). The pattern p53+/p21+ suggests wild type p53 protein able to induce the expression of p21 while the p53-/p21+ pattern suggests p53-independent p21 expression. These results are consistent with the interpretation that inactivating p53 gene mutations may be rare in HL. Comparison between bcl-2 and bax staining showed a statistically significant relationship (p<0.001) for coexpression (19 cases) or absence of expression of both proteins (28 cases) in HRS cells. In contrast, bax expression was observed in most lymphoid cells in all "reactive" lymph nodes. Since the proapoptotic bax protein may act as tumour suppressor it is possible that the absence of this protein in HRS cells in a substantial proportion of HL may confer growth advantage and play a role in their pathogenesis. This could suggest bax gene alterations in some HL since in other studies acute lymphoblastic leukaemia cell lines demonstrate bax gene mutations with loss of bax immunoexpression. Another possibility is that reduced bax expression may be due to post transcriptional regulation, as was described in lymphoma cell lines. Comparison between Rb and Ki67 staining disclosed two main deviations from the normal parallel relationship in reactive lymph nodes: a) 2 cases with low Rb and high Ki67 expression possibly reflecting loss of Rb expression due to chromosome loss or to other abnormalities in the structure or the expression of Rb gene; and b) 9 cases with high RB and low Ki67 possible reflecting an attempt of Rb protein in excess to induce cell cycle arrest. Taken together, our findings provide combined immunohistological evidence for deregulated expression of cell-cycle and apoptosis-related proteins, that may play a role in the pathogenesis of HL.
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PMID:Expression of p53, p21/waf1, bcl-2, bax, Rb and Ki67 proteins in Hodgkin's lymphomas. 1080 63

Chronic B-cell lymphocytic leukaemia (CLL) and low-grade B-cell Non Hodgkin's lymphomas (Lg-NHL) are characterized by slow accumulation of neoplastic cells arrested in the G0/G1 phase of the cell cycle. In contrast, proliferation rates are high in aggressive B-cell lymphomas (Hg-NHL). Divergent expression of cyclin-dependent kinase inhibitors (CKI) in the cell cycle may contribute to these differences. We analysed CLL as well as low and high grade B-cell NHL for expression of G1-specific and universal CKI by competitive RT-PCR and immunostaining. p16(INK4A) expression was low in all types of neoplasms. Highest p14(ARF) /p16 beta expression levels were found in normal lymphocytes. Expression of this CKI was significantly lower in CLL, but still higher in CLL than in the lymphomas (median 27 vs. 3 mRNA transcripts x 10(3), p = 0.0001). p14(ARF) /p16 beta immunostaining correlated with mRNA expression. Highest p21 mRNA levels were found in CLL, but three of four CLL with abundant p21 mRNA production were negative on immunostaining. High grade lymphomas showed markedly decreased p21 expression (3.9 in Hg-NHL vs. 12 in Lg-NHL and 29 in CLL; values expressed as mRNA transcripts x 10(3), p < 0.009). mRNA and protein expression of p27 was considerably higher in CLL than in the lymphomas. Differential CKI expression in various B-cell neoplasias may provide important biological markers, if not the molecular underpinning of their different cell cycle kinetics. Targeted interference with such genes governing cell cycle control in lymphoid neoplasia may pave the way towards new treatment strategies.
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PMID:Divergent expression of cyclin-dependent kinase inhibitors (CKI) and p14ARF/p16 beta in non-Hodgkin's lymphomas and chronic lymphocytic leukemia. 1104 28

Transforming growth factor beta1 (TGFbeta1) induces growth arrest in many cell types, including B lymphocytes. We examined the effect of TGF on cell cycle progression of a non-Hodgkin lymphoma cell line of follicular lymphoma subtype (FL). After 48 h of TGFbeta1 (10 ng/ml) treatment, a significantly increased number of DoHH2 cells was retained in G(0)/G(1) phase. We examined the level of cell cycle components, cyclins, cyclin-dependent kinases (cdk), and their inhibitors. We found that the expression of cyclin A and p21(WAF1) molecules was primarily modulated by TGFbeta1 treatment while the expression of other regulatory components, like cyclins D, cyclin E, cdk2, cdk4, and cdk6 or p15(INK4B), p16(INK4A), and p27(KIP1) was not significantly affected. We further examined expression and activity of CREB/ATF family members to examine their roles in cyclin A inhibition. The binding activity of CREB-1 and ATF-2 to the CRE region of the cyclin A promoter was almost completely abolished due to the treatment. The total level of CREB-1, ATF-2, and ATF-3 was notably reduced. Moreover, CREB-1 was dephosphorylated due to the treatment as revealed by immunoblotting. We assume that down-regulation of cyclin A was mediated by the absence of CREB/ATF activation dimers. The profound effect on the ATF family of transcription factors indicates the complexity of TGFbeta1 action on FL B malignant cells.
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PMID:Cyclin A down-regulation in TGFbeta1-arrested follicular lymphoma cells. 1108 95


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