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)

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 fatty acids (n-3 PUFAs) reduce the risk of colon cancer. Docosahexaenoic acid (DHA), a long chain polyunsaturated fatty acid (PUFAs) is a major constituent of nutrients rich in n-3 PUFAs. There are studies to indicate that colon tumor inhibition by n-3 PUFA-rich diets is, in part, mediated through modulation of signaling pathways that alter gene expression which are involved in colon tumor growth. In the present study using CaCo-2 colon cancer cell lines we examined the effects of DHA on the genetic precursors of human colon cancer at the transcription level using DNA oligonucleotide arrays. Our results indicated that DHA inhibits the growth of CaCo-2 cells and induces apoptosis. For gene expression analysis using DNA microarrays, total RNA extracted from DHA treated CaCo-2 cells was converted to cDNA, labeled with Cy5-dCTP (DHA-treated) and Cy3-dCTP (untreated cells) and used as probes for hybridization in human chip spotted with 3,800 oligonucleotides consisting of 156 functional categories. The expression profiles of genes indicated a reprogramming pattern of previously known and unknown genes and transcription factors that provided clues to the possible functional mechanism of DHA. An average of (ratios from triplicate experiments) 504 out of 3,800 genes expressed after 48 h of DHA treatment. Altered expression on the transcription factors includes down regulation of nine members of the RNA II polymerases, transcription co-repressor associated protein and enhancer binding proteins such as AP2, in addition to changes in the expression of zinc finger group of transcription factors. Activation of cytochrome c which triggers caspases was associated with the elevated expression of pro-apoptotic caspases 10, 13, 8, 5 and 9 in DHA treated cells. Activation of cyclin-dependent kinase inhibitors such as p21 (waf1/cip1), p27, p57, p19 and growth arrest specific proteins by more than 2-fold is consistent with the induction of apoptosis and inactivation of antiapototic Bcl-2 family of genes. Inactivation of prostaglandin family of genes, lipoxygenases and altered expression of peroxisome proliferators (PPARalpha and gamma) by DHA seem to indicate a lipid peroxidation-induced apoptosis in addition to effect reflected on the modification of cell cycle regulatory genes. These findings support the conclusion that a genomewide expression profiling of human colon cancer precursor genes and transcription factors provides a set of novel regulatory mechanism(s) to determine the chemopreventive efficacy of DHA and thus to prevent the inflammation and neoplasia.
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PMID:Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. 1171 97

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

Adult T cell leukemia/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL. One of the genetic events in ATLL is inactivation of tumor suppressor genes. Among many candidates for tumor suppressor genes, the main genetic events have been reported to center around the cyclin-dependent kinase inhibitors ((CDKIs) p15INK4A, p16INK4B, p18INK4C, p19INK4D, p21WAF1, p27KIP1, and p57KIP2), p53 and Rb genes; all of them play a major regulatory role during G1 to S transition in the cell cycle. Acute/lymphomatous ATLL has frequent alterations of p15 (20%) and p16 (28-67%), while chronic/smoldering ATLL has fewer abnormalities of p15 (0-13%) and p16 (5-26%). Most of these changes are deletion of the genes; fewer samples have mutations. ATLL patients with deleted p15 and/or p16 genes have significantly shorter survival than those individuals with both genes preserved. Although genetic alterations of p18, p19, p21, p27 have rarely been reported, inactivation of these genes may contribute to the development of ATLL because low expression levels of these genes seem to mark ATLL. The p53 gene is mutated in 10-50% of acute/lymphomatous ATLL. Functional impairment of the p53 protein, even if the gene has wild-type sequences, has been suggested in HTLV-I infected cells. Each of these genetic events are mainly found in acute/lymphomatous ATLL, suggesting that alterations of these genes may be associated with transformation to an aggressive phenotype. The Rb tumor suppressor gene is infrequently structurally altered, but one half of ATLL cases have lost expression of this key protein. Notably, alterations of one of the CDKIs, p53 and Rb genes appear to obviate the need for inactivation of other genes in the same pathway. A novel tumor suppressor gene on chromosome 6q may also have a critical role in the pathogenesis of ATLL. Taken together, tumor suppressor genes are frequently altered in acute/lymphomatous ATLL and their alteration is probably the driving force fueling the transition from chronic/smoldering to acute/lymphomatous ATLL.
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PMID:Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL). 1204 Apr 38

To determine the genes responsible for mediating the effects of glucocorticoids (GCs) on leukemic cells, transcriptional changes in GC-sensitive human pre-B leukemia 697 cells during GC-induced apoptosis were monitored using oligonucleotide microarrays. To circumvent the challenge of recovering mRNAs from dying cells, we compared the pattern of gene expression with that of 697 cells protected from apoptosis by transfection with bcl-2. Of the 12,000 genes examined for their response to GC, 93 genes were induced and 28 genes were repressed, many of which are known to be implicated in signal transduction, growth arrest, and transcription. These included the signal transduction-related genes encoding SOCS1, SOCS2, FKBP51, DSCR1, p56lck, and four protein kinase phosphatases. Growth arrest-related genes encoding p19(INK4d) and several Myc inhibitors were induced in response to the GC treatment. Anti-proliferative- or apoptosis-related genes encoding BTG1, BTG2, and granzyme A were also found to be transcriptionally up-regulated by GC. In addition, the regulation of genes encoding the glucocorticoid receptor and steroid receptor coactivator-1 suggested autoregulation of a GC-mediated signaling pathway.
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PMID:Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays. 1205 11

p19(INK4d), a member of the INK4 family of cyclin-dependent kinase (CDK) inhibitors, negatively regulates the cyclin D-CDK4/6 complexes, which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. To investigate the mechanism of transcriptional regulation of the p19(INK4d) gene, we characterized the 5'-flanking region of the human p19(INK4d) gene. The cap-site hunting method revealed that the transcription starts at -16 nucleotide (nt) upstream of the initiation codon. The 5'-flanking region of the human p19(INK4d) gene was ligated to a luciferase reporter gene and possessed functional promoter activity. Luciferase assay with a series of truncated 5'-flanking regions indicated that the region from -81 to -2 nt could drive the transcription of the p19(INK4d) gene. Several Sp1 and activating protein 2 binding sites are located within the region from -81 to -2 nt. Mutation of the second Sp1 binding site from -33 to -25 nt decreased the promoter activity. Collectively, it was demonstrated that the human p19(INK4d) gene is under the control of TATA-less promoter and the Sp1 binding site is involved in the transcription.
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PMID:Molecular cloning and characterization of the human p19(INK4d) gene promoter. 1206 51

To address the role of N-myc in neurogenesis and in nervous system tumors, it was conditionally disrupted in neuronal progenitor cells (NPCs) with a nestin-Cre transgene. Null mice display ataxia, behavioral abnormalities, and tremors that correlate with a twofold decrease in brain mass that disproportionately affects the cerebellum (sixfold reduced in mass) and the cerebral cortex, both of which show signs of disorganization. In control mice at E12.5, we observe a domain of high N-Myc protein expression in the rapidly proliferating cerebellar primordium. Targeted deletion of N-myc results in severely compromised proliferation as shown by a striking decrease in S phase and mitotic cells as well as in cells expressing the Myc target gene cyclin D2, whereas apoptosis is unaffected. Null progenitor cells also have comparatively high levels of the cdk inhibitors p27(Kip1) and p18(Ink4c), whereas p15(Ink4b), p21(Cip1), and p19(Ink4d) levels are unaffected. Many null progenitors also exhibit altered nuclear morphology and size. In addition, loss of N-myc disrupts neuronal differentiation as evidenced by ectopic staining of the neuron specific marker betaTUBIII in the cerebrum. Furthermore, in progenitor cell cultures derived from null embryonic brain, we observe a dramatic increase in neuronal differentiation compared with controls. Thus, N-myc is essential for normal neurogenesis, regulating NPC proliferation, differentiation, and nuclear size. Its effects on proliferation and differentiation appear due, at least in part, to down-regulation of a specific subset of cyclin-dependent kinase inhibitors.
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PMID:N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation. 1238 68

Epidemiological studies support a link between melanoma risk and UV exposure early in life, yet the molecular targets of UV's mutagenic actions are not known. By using well characterized murine models of melanoma, we provide genetic and molecular evidence that identifies components of the Rb pathway as the principal targets of UV mutagenesis in murine melanoma development. In a melanoma model driven by H-RAS activation and loss of p19(ARF) function, UV exposure resulted in a marked acceleration in melanoma genesis, with nearly half of these tumors harboring amplification of cyclin-dependent kinase (cdk) 6, whereas none of the melanomas arising in the absence of UV treatment possessed cdk6 amplification. Moreover, UV-induced melanomas showed a strict reciprocal relationship between cdk6 amplification and p16(INK4a) loss, which is consistent with the actions of UV along the Rb pathway. Most significantly, UV exposure had no impact on the kinetics of melanoma driven by H-RAS activation and p16(INK4a) deficiency. Together, these molecular and genetic data identify components of the Rb pathway as critical biological targets of UV-induced mutagenesis in the development of murine melanoma in vivo.
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PMID:Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model. 1253 79

Chromosomal numerical aberrations (CNAs), particularly regional amplifications and deletions, are a hallmark of solid tumor genomes. These genomic alterations carry the potential to convey etiologic and clinical significance by virtue of their clonality within a tumor cell population, their distinctive patterns in relation to tumor staging, and their recurrence across different tumor types. In this study, we showed that array-based comparative genomic hybridization (CGH) analysis of genome-wide CNAs can classify tumors on the basis of differing etiologies and provide mechanistic insights to specific biological processes. In a RAS-induced p19(Arf-/-) mouse model that experienced accelerated melanoma formation after UV exposure, array-CGH analysis was effective in distinguishing phenotypically identical melanomas that differed solely by previous UV exposure. Moreover, classification by array-CGH identified key CNAs unique to each class, including amplification of cyclin-dependent kinase 6 in UV-treated cohort, a finding consistent with our recent report that UVB targets components of the p16(INK4a)-cyclin-dependent kinase-RB pathway in melanoma genesis (K. Kannan, et al., Proc. Natl. Acad. Sci. USA, 21: 2003). These results are the first to establish the utility of array-CGH as a means of etiology-based tumor classification in genetically defined cancer-prone models.
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PMID:Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanoma. 1450 Mar 67

Although cyclin D2 mRNA synthesis precedes gonadotropin-induced DNA synthesis in quiescent granulosa cells in culture, it is unclear whether a similar mechanism exists for the granulosa cells of growing preantral follicles in cyclic animals. The objective was to evaluate whether the synthesis of cyclin D2 protein was a prerequisite for FSH-induced DNA synthesis in the granulosa cells of intact preantral follicles of cyclic hamsters. Preantral follicles from cyclic hamsters were cultured in the presence or absence of FSH, and cell cycle parameters were examined. FSH stimulated cyclin-dependent kinase (CDK)-4 activity by 2 h and DNA synthesis by 4 h without altering the levels of cyclin D2 in the granulosa cells. The FSH effect was mimicked by epidermal growth factor administered in vivo. Although FSH increased the levels of cyclin D2 mRNA, it also stimulated the degradation of cyclin D2 as well as p27(Kip1) and p19(INK4) proteins. FSH activation of CDK4 was mediated by cAMP and ERK-1/2. In contrast to granulosa cells in intact follicles, FSH or cAMP significantly increased cyclin D2 protein levels in cultured granulosa cells but failed to induce DNA synthesis. Collectively, these data suggest that granulosa cells of preantral follicles, which are destined to enter the S phase during the estrous cycle, contain necessary amounts of cyclin D2 and other G1 phase components. FSH stimulation results in the formation and activation of the cyclin D2/CDK4 complex leading to DNA synthesis. This mechanism may be necessary for rapid movement of follicles from preantral to antral stages during the short duration of the murine estrous cycle.
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PMID:Follicle stimulating hormone-induced DNA synthesis in the granulosa cells of hamster preantral follicles involves activation of cyclin-dependent kinase-4 rather than cyclin d2 synthesis. 1456 38

A literature review found 265 articles on testicular germ cell tumors (TGCTs) detailing the copy number of chromosomal regions and expression of 245 genes. An initial precursor stage, intratubular germ cell neoplasia (IGCN), is characterized by triploidization and an upregulation of KIT, ALPP, CCDN2, and ZNF354A, and a downregulation of CDKN2D. TGCT regularly have a series of chromosomal aberrations: a decrease in copy number at 4q21 approximately qter and 5q14 approximately qter; an increase at 7p21 approximately pter, 7q21 approximately q33, and 8q12 approximately q23 (especially high increase in seminoma); a decrease at 11p11 approximately p15 and 11q14 approximately q24; an increase at 12p11 approximately pter; a decrease at 13q14 approximately q31; an increase of 17q11 approximately q21 (only for nonseminoma); a decrease of 18q12 approximately qter; and an increase at 21q21 approximately qter, 22q11 approximately qter (only for seminoma), and Xq. Macroscopically overt TGCT is associated with a characteristic series of abnormalities in the retinoblastoma pathway including upregulation of cyclin D2 and p27 and downregulation of RB1 and the cyclin-dependent kinase inhibitors p16, p18, p19, and p21. TGCT thus has a synergistic pattern in gene expressions of the retinoblastoma pathway that is rare in other malignancies.
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PMID:Chromosomes, genes, and development of testicular germ cell tumors. 1517 50


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