Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p16 INK4A and/or p15 INK4B genes are frequently deleted in leukemias and other cancers. We have established a novel pre-B acute lymphoblastic leukemia (ALL) cell line (JKB2) with a chromosomal translocation between 9p2l and 14q32, on which p16INK4A/p15INK4B and heavy chain immunoglobulin (Ig) genes, respectively, are located. Homozygous deletions of P16INK4A/p15INK4B genes in JKB2 cells were confirmed by polymerase chain reaction, and their protein products were not detectable by Western blotting. Therefore JKB2 is the first example of an immunoglobulin heavy chain translocation associated with deletions of these genes. In JKB2 cells, cyclin-dependent kinase(CDK)4 and CDK6 formed complexes with cyclin D, due to the lack of p16, triggering phosphorylation of retinoblastoma protein (pRB) and continuous cell proliferation. Moreover, the growth of JKB2 cells was partially inhibited by TGF beta or IL-7, accompanied by decreased CDK4 and CDK6 expression, increased p2l and p27 expression, decreased p27 binding to CDK4/CDK6, and increased binding of p27 to CDK2. In addition, IL-7 both inhibited proliferation and induced differentiation of JKB2 cells. These studies suggest that a t(9;14)(p21;q32) chromosomal translocation can result in deletion of both p16 INK4A and p15 INK4B genes in pre-B ALL, and that the JKB2 cell line therefore provides a model for the study of leukemogenesis related to abnormalities in chromosome 9p2l. Moreover, they suggest that TGF-beta can, suppress JKB2 cell growth in a p15-independent mechanism.
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PMID:A novel pre-B acute lymphoblastic leukemia cell line with chromosomal translocation between p16(INK4A)/p15(INK4B) tumor suppressor and immunoglobulin heavy chain genes: TGFbeta/IL-7 inhibitory signaling mechanism. 884 92

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

In this study the induction of stress activated protein kinase (SAPK) activity by protein synthesis inhibitors was shown not to inhibit cellular proliferation. Anisomycin induced strong SAPK activity at non-inhibitory concentrations for either protein or DNA synthesis, while the other two inhibitors, emetine and cycloheximide, blocked cell cycle progression without strong SAPK induction. With all three inhibitors, the induction of SAPK activity was always accompanied by protein synthesis inhibition to some extent. Stimulation of mRNA expression of the genes c-jun, c-fos and c-myc correlated well with SAPK induction, but not with cell cycle inhibition. With concentrations of each inhibitor able to block DNA synthesis, no induction of message for the cyclin dependent kinase inhibitor waf-1 was observed; while induction of gadd45 message indicated that the cells might be responding to growth-arrest or DNA damage. The inability of microinjected E2F/DP1 transcription factor proteins to overcome the inhibition of DNA synthesis induced by protein synthesis inhibitors indicate that blockage of an early event in cell cycle progression had occurred. These results indicate that the SAPK induction by protein synthesis inhibitors has no proliferative consequences.
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PMID:Activation of JNK/SAPK pathway is not directly inhibitory for cell cycle progression in NIH3T3 cells. 895 84

Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1 gene overexpression. Some aggressive variants of MCL have been described with blastic or large cell morphology, higher proliferative activity, and shorter survival. The cyclin-dependent kinase inhibitors (CDKIs) p21Waf1 and p16INK4a have been suggested as candidates for tumor-suppressor genes. To determine the role of p21Waf1 and p16INK4a gene alterations in MCLs, we examined the expression, deletions, and mutations of these genes in a series of 24 MCLs, 18 typical, and 6 aggressive variants. Loss of expression and/or deletions of p21Waf1 and p16INK4a genes were detected in 4 (67%) aggressive MCLs but in none of the typical variants. Two aggressive MCLs showed a loss of p16INK4a expression. These cases showed homozygous deletions of p16INK4a gene by Southern blot analysis. An additional aggressive MCL in which expression could not be examined showed a hemizygous 9p12 deletion. Loss of p21Waf1 expression at both protein and mRNA levels was detected in an additional aggressive MCL. No p21Waf1 gene deletions or mutations were found in this case. The p21Waf1 expression in MCLs was independent of p53 mutations. The two cases with p53 mutations showed p21Waf1 and p16INK4a expression whereas the 4 aggressive MCLs with p16INK4a and p21Waf1 gene alterations had a wild-type p53. p21Waf1 and p16INK4a were expressed at mRNA and protein levels in all typical MCLs examined. No gene deletions or point mutations were found in typical variants. Two typical MCLs showed an anomalous single-stranded conformation polymorphism corresponding to the known polymorphisms at codon 148 of p16INK4a gene and codon 31 of p21Waf1 gene. These findings indicate that p21Waf1 and p16INK4a alterations are rare in typical MCLs but the loss of p21Waf1 and p16INK4a expression, and deletions of p16INK4a gene are associated with aggressive variants of MCLs, and they occur in a subset of tumors with a wild-type p53 gene.
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PMID:Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas. 897 1

To study the structural integrity of the cyclin-dependent kinase inhibitors known as INK4A (p16), INK4B (p15) and INK4C (p18) in multiple myeloma, we examined 20 primary myeloma samples (including one case of plasma cell leukaemia) using polymerase chain reaction-single strand conformation polymorphism, and 17 samples were examined by Southern blot analysis. The plasma cell leukaemia sample had homozygous deletions of the p15 and p16 genes (6%). One myeloma case had a p15 gene homozygous deletion (6%) with an intact p16 gene. This sample also had a p18 homozygous deletion, suggesting that the deletion of both genes may be important in either the development or progression of myeloma. No point mutations of these INK4 genes were found in the 20 samples. This is the first report that indicates that deletions of p15, p16 and p18 genes occur in some individuals with multiple myeloma (2/17 cases).
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PMID:Analysis of the p16INK4A, p15INK4B and p18INK4C genes in multiple myeloma. 901 94

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

The expression of cyclins (A, B1, D1, D3, E), cyclin-dependent kinases (CDK2(3), CDK4), and the cyclin-dependent kinase inhibitors (CDKIs) p16(INK4A) and p21(CIP1) was studied in 9 malignant human astrocytoma cell lines using northern blot analysis, immunocytochemistry, and immunoblotting to see if their altered expression contributed to astrocytoma proliferation. Steady state cell cycle mRNA expression was analyzed in unsynchronized tumor cells, and cell cycle phase-specific gene expression was analyzed in 3 synchronized cell lines. Analysis of steady state expression revealed increased levels of several different cyclin transcripts and CDKs in a number of astrocytoma cell lines compared with normal human brain tissue or cultured fibroblasts. We confirm previous reports identifying loss of p16(INK4A) in astrocytomas, as a p16(INK4A) transcript was identified in only 2 cell lines and protein in 1 cell line. However, we now show that p21(CIP1) expression was also diminished relative to normal fibroblasts in all astrocytoma cell lines studied regardless of p53 mutation status. Analysis of synchronized astrocytoma cells revealed altered timing of mRNA expression of several cyclins. Immunocytochemistry revealed a generalized increase in immunoreactivity of astrocytoma cells for most cyclins and CDKs compared with human fibroblasts. Immunoblotting also revealed increased expression of cyclin proteins in a number of astrocytoma cell lines. These data suggest that increased expression of cyclins and CDKs, and decreased expression of CDKIs by human astrocytoma cell lines may contribute to their increased proliferative state. In addition, our data show that alterations in cell cycle genes in astrocytomas are not confined to the cyclin D1-CDK4-pRb axis.
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PMID:Cyclin and cyclin-dependent kinase expression in human astrocytoma cell lines. 905 43

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal blood disorders characterized by dyshematopoiesis with a frequent evolution to acute leukemia. Chromosomal deletions rather than translocations are the predominant karyotypic abnormalities in MDS, suggesting a recessive mechanism in the pathogenesis of MDS, such as inactivation of tumor suppressor genes. A group of cyclin-dependent kinase inhibitors, p15 (INK4B), p16 (INK4A), p18 (INK4C) and p19 (INK4D), are candidate tumor suppressor genes. To determine whether genetic alterations of these genes play an important role in the development and/or progression of MDS, we examined 46 samples from MDS patients by Southern blotting, single-strand-conformation polymorphism (SSCP) using polymerase chain reaction (PCR) and sequencing of DNA. These samples included 13 refractory anemias (RA), four refractory anemias with ringed sideroblasts (RARS), 16 refractory anemias with an excess of blasts (RAEB), eight refractory anemias with an excess of blasts in transformation (RAEB-T) and five chronic myelomonocytic leukemia (CMMoL) samples. Except for allelic polymorphisms or silent point mutations, no alterations of coding regions of these four CDKI genes were identified. In summary, genetic abnormalities of the p15, p16, p18 and p19 genes are rare events in the development and/or progression of MDS.
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PMID:Molecular analysis of the cyclin-dependent kinase inhibitor genes, p15, p16, p18 and p19 in the myelodysplastic syndromes. 911 Nov 68

Although thrombopoietin (TPO) is known to play a fundamental role in both megakaryopoiesis and thrombopoiesis, the molecular mechanism of TPO-induced megakaryocytic differentiation is not known. In a human megakaryoblastic leukemia cell line, CMK, that showed some degree of megakaryocytic differentiation after culture with TPO, the cyclin-dependent kinase (Cdk) inhibitor p21(WAF1/Cip1), but not p27(Kip1), p16(INK4A), p15(INK4B), or p18(INK4C), was found to be upregulated in an immediately early response to TPO. The expression of p21 was found to be sustained over a period of 5 days by treatment with TPO in large polyploid cells that developed in response to TPO, but not in small undifferentiated cells, indicating a close correlation between the ligand-induced differentiation and p21 induction in CMK cells. To examine potential roles of Cdk inhibitors in megakaryocytic differentiation, CMK cells were transfected with the p21, p27, or p16 gene, together with a marker gene, beta-galactosidase, and were cultured with medium alone for 5 days. The ectopic expression of p21 or p27 but not of p16 led to induction of megakaryocytic differentiation of CMK cells. Overexpression of the N-terminal domain (amino acids [aa] 1 to 75) of p21 was sufficient to induce megakaryocytic differentiation, whereas that of the C-terminal domain (aa 76 to 164) had little or no effect on morphological features. Furthermore, we found that although TPO induced tyrosine phosphorylation of both STAT3 and STAT5 in CMK cells, only STAT5 showed binding activities to potential STAT-binding sites that locate in the promoter region of p21 gene (p21-SIE sites), thereby leading to transactivation of p21. These results suggested that p21 induction, possibly mediated through activated STAT5, could play an important role in TPO-induced megakaryocytic differentiation.
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PMID:Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21(WAF1/Cip1) by STAT5. 911 65

To provide a state-of-the-art summary of currently available data about the genetics of cutaneous melanoma and nevi, we reviewed the pertinent literature and outlined the important findings on genetic analyses. Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, seminal studies by investigators at the National Cancer Institute and the University of Pennsylvania identified dysplastic nevi (DN) as an important melanoma precursor, suggested an autosomal dominant mode of inheritance for both melanoma and DN, and proposed that a melanoma-susceptibility gene (CMM1) was located on chromosome 1p36. This gene assignment has not yet been confirmed by independent investigators. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed independently, and the cell cycle regulator p16INK4a has been proposed as a candidate gene; germline mutations in this gene have been identified in about half of melanoma-prone families. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have recently been described in two melanoma kindreds; this finding likely represents a third melanoma gene. A heritable determinant for total nevus number has been suggested, as has the presence of a major gene responsible for total nevus density in melanoma-prone families. An autosomal dominant mode of inheritance for DN has been proposed, and evidence suggests that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk for melanoma, these family studies suggest that relatives of persons with DN should be examined for DN and for melanoma. Overall, genetic determinants have a major role in the pathogenesis of normal nevi, DN, and melanoma. Elucidating the molecular basis of these genetic events promises to enhance melanoma risk reduction strategies and thereby reduce melanoma-associated mortality.
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PMID:Genetics of cutaneous melanoma and nevi. 914 91


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