Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogenic signals stimulate cell division by activating cyclin/cyclin-dependent kinase (CDK) complexes. Their timely regulation ensures proper cell cycle progression. It is therefore not surprising that cyclin/CDK complexes are integrators of multiple signals from both the extracellular environment and intracellular cues. Important regulators of cyclin/CDKs are the CDK inhibitors that have attracted attention due to their association with disease. p27(KIP1) is a CDK inhibitor that controls CDK activity throughout the cell cycle. As a CDK inhibitor, p27(KIP1) has tumor suppressor activity. Besides CDKs, p27(KIP1) regulates additional cellular processes, including cell motility, some of which seem to mediate oncogenic activities of p27(KIP1). These activities of p27(KIP1) are regulated through multiple phosphorylation sites, targeted by several signal transduction pathways. Understanding functions and regulation of p27(KIP1) will be important to determine which isoform of p27(KIP1) has anti- or pro-tumorigenic activities. Such knowledge might be of prognostic value and may offer novel therapeutic windows.
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PMID:Post-translational regulation of the tumor suppressor p27(KIP1). 1863 26

Resistance to growth suppression by TGF-beta1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G(1) cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma.
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PMID:CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells. 1920 32

Prostate cancer (PC), which responds well to androgen ablation initially, invariably progresses to treatment resistance. The so-called androgen-independent PC is also a concern, since there is no effective therapy so far. Nkx3.1 is a putative prostate tumor suppressor that is expressed exclusively in the prostate under the regulation of androgen, and p27(KIP1) functions as a cell proliferation inhibitor and apoptosis trigger by disrupting the cyclin-dependent kinase (CDK)-cyclin complex. Lack of expressions of Nkx3.1 and/or p27(KIP1) have been detected in most advanced PC and is associated with poor clinical progression. Here, we show that endogenous expressions of both Nkx3.1 and p27(KIP1) are lost in the androgen-independent PC3 PC cells, while remaining intact in LNCaP PC cells, which contain functional androgen receptor (AR) and are hormone-responsive. Ectopic restoration of either Nkx3.1 or p27(KIP1) in PC3 cells results in reduced cell proliferation, and increased cell death. Both effects are synergistically enhanced when the two molecules are coexpressed. p27(KIP1) overexpression in PC3 results in increased cell population ceased at the G0/G1 phase, and this cell-cycle-arresting effect is significantly enhanced by the coexpression of Nkx3.1. Flow cytometry further revealed that Nkx3.1 and p27(KIP1) also cooperatively render more PC3 cells undergoing apoptosis. Consistently, the coexpression of Nkx3.1 and p27(KIP1) leads to the decreased expression of Bcl-2 oncogene and a concomitantly upregulated Bax expression. It also activates caspase 3 and leads to increased cleavage of PARP. Our findings thus reveal the crucial relevance of the combined antiproliferative and proapoptotic activities of Nkx3.1 and p27(KIP1) in androgen-independent PC cells, and further suggest that a combined, rather than single gene manipulation may be of clinical value for hormone-refractory PC.
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PMID:Nkx3.1 and p27(KIP1) cooperate in proliferation inhibition and apoptosis induction in human androgen-independent prostate cancer cells. 1926 49

Isoliquiritigenin (ISL), a flavonoid chalcone that is present in licorice, shallot, and bean sprouts, is known to have antitumorigenic activities. The present study examined whether ISL alters prostate cancer cell cycle progression. DU145 human and MatLyLu (MLL) rat prostate cancer cells were cultured with various concentrations of ISL. In both DU145 and MLL cells treated with ISL, the percentage of cells in the G1 phase increased, and the incorporation of [(3)H]thymidine decreased. ISL decreased the protein levels of cyclin D1, cyclin E, and cyclin-dependent kinase (CDK) 4, whereas cyclin A and CDK2 expressions were unaltered in cells treated with ISL. The expression of the CDK inhibitor p27(KIP1) was increased in cells treated with 20 micromol/L ISL. In addition, treatment of cells with 20 micromol/L ISL for 24 hours led to G2/M cell cycle arrest. Cell division control (CDC) 2 protein levels remained unchanged. The protein levels of phospho-CDC2 (Tyr15) and cyclin B1 were increased, and the CDC25C level was decreased by ISL dose-dependently. We demonstrate that ISL promotes cell cycle arrest in DU145 and MLL cells, thereby providing insights into the mechanisms underlying its antitumorigenic activities.
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PMID:Induction of cell cycle arrest in prostate cancer cells by the dietary compound isoliquiritigenin. 1929 90

Phorbol 12-myristate 13-acetate (PMA) modulates cell proliferation and survival by activating several intracellular signaling pathways. Protein kinase C (PKC) plays a key role in PMA-induced growth arrest of non-small cell lung cancer (NSCLC) cells. Kruppel-like transcription factor 6 (KLF6), which is associated with negative control of cell proliferation, is downregulated in many cancers, including NSCLC. In this study, we found that KLF6 is downregulated in 17 lung cancer cell lines and in cells representing early stages of lung cancer development. Moreover, PMA induced cell growth arrest through KLF6 induction in H358 NSCLC cells. The increase in KLF6 by PMA was associated with upregulation of the cyclin-dependent kinase inhibitors (CDKIs) p21(WAF1/CIP1) and p27(KIP1). In addition, inhibition of PKC or JNK activation decreased PMA-induced KLF6 induction and activation of PKC alone by Bryostatin-1 and Thymeleatoxin increased KLF6 levels. Moreover, siRNA-mediated knockdown of KLF6 reduced PMA-induced cell growth inhibition concomitantly with decreased expression of both p21(WAF1/CIP1) and p27(KIP1), and in accordance, overexpression of KLF6 alone upregulated both CDKIs protein levels. Our results demonstrate the induction of the tumor suppressor KLF6 following PKC activation and its importance for PMA-mediated cancer cell growth arrest.
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PMID:Activation of protein kinase C by phorbol 12-myristate 13-acetate suppresses the growth of lung cancer cells through KLF6 induction. 1933 10

HTLV-1 Tax can induce senescence by up-regulating the levels of cyclin-dependent kinase inhibitors p21(CIP1/WAF1) and p27(KIP1). Tax increases p27(KIP1) protein stability by activating the anaphase promoting complex/cyclosome (APC/C) precociously, causing degradation of Skp2 and inactivation of SCF(Skp2), the E3 ligase that targets p27(KIP1). The rate of p21(CIP1/WAF1) protein turnover, however, is unaffected by Tax. Rather, the mRNA of p21(CIP1/WAF1) is greatly up-regulated. Here we show that Tax increases p21 mRNA expression by transcriptional activation and mRNA stabilization. Transcriptional activation of p21(CIP1/WAF1) by Tax occurs in a p53-independent manner and requires two tumor growth factor-beta-inducible Sp1 binding sites in the -84 to -60 region of the p21(CIP1/WAF1) promoter. Tax binds Sp1 directly, and the CBP/p300-binding activity of Tax is required for p21(CIP1/WAF1) trans-activation. Tax also increases the stability of p21(CIP1/WAF1) transcript. Several Tax mutants trans-activated the p21 promoter, but were attenuated in stabilizing p21(CIP1/WAF1) mRNA, and were less proficient in increasing p21(CIP1/WAF1) expression. The possible involvement of Tax-mediated APC/C activation in p21(CIP1/WAF1) mRNA stabilization is discussed.
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PMID:Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization. 1935 50

Id2 is a member of the helix-loop-helix (HLH) family of transcription regulators known to antagonize basic HLH transcription factors and proteins of the retinoblastoma tumor suppressor family and is implicated in the regulation of proliferation, differentiation, apoptosis and carcinogenesis. To investigate its proposed role in tumorigenesis, Id2 or deletion mutants were re-expressed in Id2(-/-) dermal fibroblasts. Ectopic expression of Id2 or mutants containing the central HLH domain increased S-phase cells, cell proliferation in low and normal serum and induced tumorigenesis when grafted or subcutaneously injected into athymic mice. Similar to their downregulation in human tumors, the expression of cyclin-dependent kinase inhibitors p27(KIP1) and p15(INK4b) was decreased by Id2; the former by downregulation of its promoter by the Id2 HLH domain-mediated sequestration of E12/E47. Re-expression of p27(KIP1) in Id2-overexpressing cells reverted the hyperproliferative and tumorigenic phenotype, implicating Id2 as an oncogene working through p27(KIP1). These results tie together the previously observed misregulation of Id2 with a novel mechanism for tumorigenesis.
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PMID:Sequestration of E12/E47 and suppression of p27KIP1 play a role in Id2-induced proliferation and tumorigenesis. 1945 Nov 88

We have examined whether and by what mechanism piceatannol inhibits cell cycle progression in DU145 cells. The treatment of cells with piceatannol for 24h resulted in an increase in the percentage of cells in G1 phase and dose-dependent decreases in [(3)H]thymidine incorporation, as well as in protein levels of cyclin A, cyclin D1, and cyclin-dependent kinase (CDK)2 and CDK4. Piceatannol exerted no effect on the levels of p21(WAF1/CIP1) or p27(KIP1). Piceatannol reduced CDK4 and CDK2 activity. These results indicate that delaying G1 cell cycle progression contributes to the piceatannol-mediated inhibition of DU145 cell growth, which may be mediated via the inhibition of CDK activity.
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PMID:Piceatannol, a natural stilbene from grapes, induces G1 cell cycle arrest in androgen-insensitive DU145 human prostate cancer cells via the inhibition of CDK activity. 1948 74

Cell cycle regulation by differentiation signals is critical for eukaryote development. We investigated the roles of bone morphogenetic protein (BMP)-4, an important stimulator of osteoblast differentiation and bone formation, in regulating cell cycle distribution in four osteoblast-like cell lines and mouse primary osteoblasts, and the underlying mechanisms. In all cells used, BMP-4 induced G(0)/G(1) arrest. The molecular basis of the BMP-4 effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 cells. BMP-4 induced p21(CIP1) and p27(KIP1) expressions and hence cell differentiation but had no effects on the expressions of cyclins A, B1, D1, and E, cyclin-dependent protein kinase-2, -4, and -6. Using specific small interfering RNA (siRNA), we found that BMP-4-induced G(0)/G(1) arrest, and p21(CIP1) and p27(KIP1) expressions were mediated by BMP receptor type IA (BMPRIA)-specific Sma- and Mad-related protein (Smad)1/5. BMP-4 induced transient phosphorylations of ERK; transfection of MG63 cells with ERK2, but not ERK1, -specific siRNA inhibited the BMP-4-induced responses in MG63 cells. Pretreatment of MG63 cells with Arg-Gly-Asp-Ser, which blocks the cell-extracellular matrix interaction, or transfection with beta(3) integrin-specific siRNA inhibited BMP-4-induced ERK and Smad1/5 phosphorylations. BMP-4 induced transient increases in associations of beta(3)-integrin with focal adhesion kinase and Shc, the dominant-negative mutants of which inhibited BMP-4-induced ERK and Smad1/5 phosphorylations. Our results indicate that BMP-4 induces G(0)/G(1) arrest and hence differentiation in osteoblast-like cells through increased expressions of p21(CIP1) and p27(KIP1), which are mediated by BMPRIA-specific Smad1/5. The extracellular matrix/beta(3) integrin/ focal adhesion kinase/Shc/ERK2 signaling pathway is involved in these BMP-4-induced responses in osteoblast-like cells.
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PMID:BMP-4 induction of arrest and differentiation of osteoblast-like cells via p21 CIP1 and p27 KIP1 regulation. 1981 88

Epidemiological studies suggest that human papillomavirus (HPV)-infected women who smoke face an increased risk for developing cervical cancer. We have previously reported that exposure of HPV-positive organotypic cultures to benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, resulted in enhanced viral titers. Since BaP is known to deregulate multiple pathways of cellular proliferation, enhanced virion synthesis could result from carcinogen/host cell interaction. Here, we report that BaP-mediated upregulation of virus synthesis is correlated to an altered balance between cell cycle-specific cyclin-dependent kinase (CDK) activity profile compared with controls. Specifically, BaP treatment increased accumulation of hyperphosphorylated retinoblastoma protein (pRb) which coincided with increased cdc2/CDK1 kinase activity, but which further conflicted with the simultaneous upregulation of CDK inhibitors p16(INK4) and p27(KIP1), which normally mediate pRb hypophosphorylation. In contrast, p21(WAF1) and p53 levels remained unchanged. Under these conditions, CDK6 and CDK2 kinase activities were decreased, whereas CDK4 kinase activity remained unchanged. The addition of purvalanol A, a specific inhibitor of CDK1 kinase, to BaP-treated cultures, resulted in the production of noninfectious HPV type 31b (HPV31b) particles. In contrast, infectivity of control virus was unaffected by purvalanol A treatment. BaP targeting of CDK1 occurred independently of HPV status, since BaP treatment also increased CDK1 activity in tissues derived from primary keratinocytes. Our data indicate that HPV31b virions synthesized in the presence of BaP were dependent on BaP-mediated alteration in CDK1 kinase activity for maintaining their infectivity.
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PMID:Downregulation of Cdc2/CDK1 kinase activity induces the synthesis of noninfectious human papillomavirus type 31b virions in organotypic tissues exposed to benzo[a]pyrene. 2018 98


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