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)

Proteases are known to play important roles in cell growth control, although the underlying mechanisms are still poorly understood. Here we show that the protease inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal induced cell cycle arrest in platelet-derived growth factor-stimulated human fibroblasts at the G1/S boundary of the cell cycle by inhibiting the proteasome. Inhibition of the proteasome resulted in accumulation of the tumor suppressor p53, which was followed by an increase in the amount of the cyclin-dependent kinase-inhibitor p21. As a consequence, both phosphorylation and activity of the cyclin-dependent kinase 2/cyclin E complex were inhibited. We further observed that the retinoblastoma gene product, pRb, remained in the hypophosphorylated state, thus preventing cells from progression into the S-phase. These studies strongly support the hypothesis that the proteasome is a key regulator in the G1-phase of cell cycle progression.
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PMID:p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. 885 63

The sequential transcriptional activation of cyclins, the regulatory subunits of cell cycle specific kinases, regulates progress through the cell cycle. In mitogen-stimulated cells cyclin D1 induction in early G1 is followed by induction of cyclin E, activation of the cyclin-dependent kinase Cdk2, and hyperphosphorylation of the retinoblastoma gene product (pRB) in mid-to-late G1 phase. T-47D breast cancer cells expressing cyclin D1 under the control of a metal-responsive metallothionein promoter were used to determine whether Cdk2 activation and pRB hyperphosphorylation are consequences of cyclin D1 induction. A 4-5-fold increase in cyclin D1 protein abundance was followed by approximately 2-fold increases in cyclin E protein abundance and Cdk2 activity and by hyperphosphorylation of pRB. These responses were apparent approximately 3 h after the increase in cyclin D1 protein, and approximately 3 h prior to the entry of cyclin D1-stimulated cells into S phase 12 h after zinc treatment. Cyclin D1 immunoprecipitates contained Cdk4 but no detectable Cdk2 and displayed pRb but not histone H1 kinase activity. Cdk2 activation was therefore likely to be due to increased abundance of cyclin E/Cdk2 complexes rather than formation of active cyclin D1/Cdk2 complexes. The sequence of events following zinc induction of cyclin D1 thus mimicked that following mitogen induction of cyclin D1. These data show that cyclin D1 induction is sufficient for Cdk2 activation and pRB hyperphosphorylation in T-47D human breast cancer cells, providing evidence that cyclin D1 induction is a critical event in G1 phase progression.
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PMID:Inducible expression of cyclin D1 in T-47D human breast cancer cells is sufficient for Cdk2 activation and pRB hyperphosphorylation. 886 12

Cell proliferation control is ensured by a group of proteins named cyclin-dependent kinases (CDKs), the activation of which is dependent on phosphorylation and cyclin association. In parallel, these CDKs are negatively controlled by two distinct groups of inhibitory proteins, the cyclin-dependent kinase inhibitors (CKIs). The first group, including p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d, is specific for the G1 CDKs, CDK4 and CDK6, inhibiting the kinase activity of cyclin D/CDK4-CDK6 complexes on pRb. p16Ink4a, down-regulated by pRb, inhibits G1 CDKs by competition with cyclin D; p15Ink4b, the synthesis of which is induced by TGF beta, seems to be a mediator of TGF beta-mediated cell cycle arrest. Furthermore, p18Ink4c inhibits CDK6 phosphorylation and activation by CAK. The second CKIs family is constituted by p21Waf1, p27Kip1 and p57Kip2. Their inhibitory action concerns a large range of cyclin/CDK complexes involved in G1 and S phase. p21Waf1, induced in part by p53, is up-regulated by senescence, DNA damage and cellular differentiation. p21Waf1 forms quaternary complexes with CDKs, cyclins and PCNA. Its inhibitory action, preventing CDK from phosphorylation, depends on the stoichiometry of the components. As p15Ink4b, p27Kip1 causes late G1 cell cycle arrest after TGF beta treatment and contact inhibition. The implications of CKIs in hematological malignancies are function of deletions or mutations of their genes. p16Ink4a and p15Ink4b genes, localized on 9p21, present frequent homozygous deletions in ALL T, ATL and lymphoblastic acutisation of CML. The other CKIs present very rare homozygous deletions or mutations, particularly p21Waf1 and p27Kip2. However, reduction of inhibitory activity due to hemizygous deletions might favour leukemogenesis.
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PMID:Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies. 889 23

Viral oncoproteins that inactivate the retinoblastoma tumor suppressor protein (pRb) family both block skeletal muscle differentiation and promote cell cycle progression. To clarify the dependence of terminal differentiation on the presence of the different pRb-related proteins, we have studied myogenesis using isogenic primary fibroblasts derived from mouse embryos individually deficient for pRb, p107, or p130. When ectopically expressed in fibroblasts lacking pRb, MyoD induces an aberrant skeletal muscle differentiation program characterized by normal expression of early differentiation markers such as myogenin and p21, but attenuated expression of late differentiation markers such as myosin heavy chain (MHC). Similar defects in MHC expression were not observed in cells lacking either p107 or p130, indicating that the defect is specific to the loss of pRb. In contrast to wild-type, p107-deficient, or p130-deficient differentiated myocytes that are permanently withdrawn from the cell cycle, differentiated myocytes lacking pRb accumulate in S and G2 phases and express extremely high levels of cyclins A and B, cyclin-dependent kinase (Cdk2), and Cdc2, but fail to readily proceed to mitosis. Administration of caffeine, an agent that removes inhibitory phosphorylations on inactive Cdc2/cyclin B complexes, specifically induced mitotic catastrophe in pRb-deficient myocytes, consistent with the observation that the majority of pRb-deficient myocytes arrest in S and G2. Together, these findings indicate that pRb is required for the expression of late skeletal muscle differentiation markers and for the inhibition of DNA synthesis, but that a pRb-independent mechanism restricts entry of differentiated myocytes into mitosis.
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PMID:Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle. 889

We show here that c-Myc antagonizes the cyclin-dependent kinase (CDK) inhibitor p27Kip1. p27 expressed from recombinant retroviruses in Rat1 cells associated with and inhibited cyclin E/CDK2 complexes, induced accumulation of the pRb and p130 proteins in their hypophosphorylated forms, and arrested cells in G1. Prior expression of c-Myc prevented inactivation of cyclin E/CDK2 as well as dephosphorylation of pRb and p130, and allowed continuous cell proliferation in the presence of p27. This effect did not require ubiquitin-mediated degradation of p27. Myc altered neither the susceptibility of cyclin E/CDK2 to inhibition by p27, nor the intrinsic CDK-inhibitory activity of p27, but induced sequestration of p27 in a form unable to bind cyclin E/CDK2. Neither Myc itself nor other G1-cyclin/CDK complexes were directly responsible for p27 sequestration. Retroviral expression of G1 cyclins (D1-3, E or A) or of the Cdc25A phosphatase did not overcome p27-induced arrest. Growth rescue by Myc required dimerization with Max, DNA binding and an intact transcriptional activation domain, as previously shown for cellular transformation. We propose that this activity is mediated by the product of an as yet unknown Myc-Max target gene(s) and represents an essential aspect of Myc's mitogenic and oncogenic functions.
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PMID:Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. 897 86

Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G1/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.
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PMID:Cyclin E, a redundant cyclin in breast cancer. 898 90

The major transforming protein of human papillomaviruses (HPVs) is encoded by the E7 gene. This protein cooperates with activated oncogenes to transform primary rodent cells and with the viral E6 gene to immortalize primary human keratinocytes. Numerous cellular targets of HPV E7 have now been identified including pRb, p107, cyclin A, TATA box binding protein (TBP), and members of the AP-1 transcription factor family. As with Adenovirus E1a, many of these interactions are important for the ability of E7 to transform cells. Recent studies have demonstrated that Adenovirus E1a can also inhibit the transcriptional activity of the cellular tumor suppressor protein, p53. We have performed a series of analyses to determine whether HPV E7 proteins share this characteristic. We show that HPV E7 proteins derived from both benign and tumor-associated HPV types are able to inhibit p53 transcriptional activity. Mutational analysis of the HPV-16 E7 protein reveals that a key domain involved in mediating this activity is the casein kinase II (CKII) recognition site, which has been shown to modulate E7 binding to TBP. We further show that E7 does not bind to p53 directly, but will do so in the presence of exogenously added TBP and that this binding is increased following CKII phosphorylation. These results suggest that the E7-TBP interaction may be responsible for inhibiting p53 transcriptional activity.
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PMID:Repression of p53 transcriptional activity by the HPV E7 proteins. 900 83

Among the p53-regulated genes that have been identified thus far, cyclin G is a relatively recent one. We conducted a series of experiments aimed at elucidating cyclin G function. Ectopic overexpression of cyclin G in human RKO colon carcinoma cells accelerated cell growth. Transfection of normal human fibroblasts with the cyclin G expression vector promoted clonal expansion. Cyclin G immune complexes isolated from the transfected cells exhibited appreciable levels of cyclin-dependent kinase activity, as evidenced using histone H1 as a substrate. The retinoblastoma protein, pRb, was detectable in cyclin G immune complexes, raising the possibility that Rb may be one mediator of cyclin G action. Cyclin G-overexpressing cells were more sensitive to cisplatin cytotoxicity than the parent cells, probably because cyclin G overexpression overrides cell cycle checkpoint(s). Overexpression of another p53-regulated gene, GADD45, by contrast, protected cells from cisplatin killing. These findings suggest that different downstream effectors of the p53 pathway may exert different effects on cellular survival after treatment with cancer chemotherapy drugs such as cisplatin.
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PMID:The p53-regulated cyclin G gene promotes cell growth: p53 downstream effectors cyclin G and Gadd45 exert different effects on cisplatin chemosensitivity. 901 7

Cell cycle arrest and cell death are tightly coupled to terminal differentiation of B cells to plasma cells in vivo. This process was recapitulated in vitro by stimulation of IgG-bearing human B lymphoblastoid cells with interleukin-6 (IL-6), which led to orderly cell cycle arrest, differentiation, and apoptosis. In terminally differentiated plasmacytoid cells, phosphorylation of pRb was suppressed, correlating with the activation of the D-type cyclin-dependent kinase (CDK) inhibitors p18(INK4c) and p21(WAF1/CIP1). The expression of CDK6, however, remained unchanged. Activation of p18 by IL-6 was rapid, concomitant with marked enhancement of its association with CDK6 and cell cycle arrest. Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest. Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6.
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PMID:Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6. 905 36

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


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