Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferons (IFN) regulate transcription of certain genes playing a role in cell proliferation. Targets of IFN action may include tumor suppressor genes such as the retinoblastoma (RB) gene and cytokines such as transforming growth factor beta 1 (TGF beta 1) and IFN beta which are inhibitors of epithelial cell proliferation. Using reverse transcription followed by PCR amplification, an increase of those growth inhibitory gene mRNA levels (TGF beta 1, IFN beta and RB) were found after interferon treatment in condylomas harboring non-oncogenic human papilloma virus (HPV 6/11) types, in an oncogenic HPV 16-containing cell line, and in a HPV negative, epidermoid carcinoma cell line. In addition, immunodetection by Western blot demonstrated a higher proportion of underphosphorylated (active form) retinoblastoma gene protein (pRB) after IFN treatment due to the decrease in the phosphorylating cdc2 kinase levels. Changes in the phosphorylation pattern of pRB together with the increased expression of those inhibitory genes represent a growth inhibited state in those cells as demonstrated by diminished c-myc expression. Since the extent of c-myc inhibition was significantly lower in the case of oncogenic HPV infection, a role of viral oncoproteins in abrogation of the antiproliferative effect of IFN therapy could be considered. These results demonstrate a new mechanism via which IFNs exert their antiproliferative effect on HPV-infected cells by affecting the expression and phosphorylation of the RB tumor suppressor gene, through the inhibitory TGF beta 1/IFN beta cytokine pathway.
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PMID:Interferon treatment enhances the expression of underphosphorylated (biologically-active) retinoblastoma protein in human papilloma virus-infected cells through the inhibitory TGF beta 1/IFN beta cytokine pathway. 751 81

Peripheral blood T lymphocytes require two sequential mitogenic signals to reenter the cell cycle from their natural, quiescent state. One signal is provided by stimulation of the T-cell antigen receptor, and this induces the synthesis of both cyclins and cyclin-dependent kinases (CDKs) that are necessary for progression through G1. Antigen receptor stimulation alone, however, is insufficient to promote activation of G1 cyclin-Cdk2 complexes. This is because quiescent lymphocytes contain an inhibitor of Cdk2 that binds directly to this kinase and prevents its activation by cyclins. The second mitogenic signal, which can be provided by the cytokine interleukin 2, leads to inactivation of this inhibitor, thereby allowing Cdk2 activation and progression into S phase. Enrichment of the Cdk2 inhibitor from G1 lymphocytes by cyclin-CDK affinity chromatography indicates that it may be p27Kip1. These observations show how sequentially acting mitogenic signals can combine to promote activation of cell cycle proteins and thereby cause cell proliferation to start. CDK inhibitors have been shown previously to be induced by signals that negatively regulate cell proliferation. Our new observations show that similar proteins are down-regulated by positively acting signals, such as interleukin 2. This finding suggests that both positive and negative growth signals converge on common targets which are regulators of G1 cyclin-CDK complexes. Inactivation of G1 cyclin-CDK inhibitors by mitogenic growth factors may be one biochemical pathway underlying cell cycle commitment at the restriction point in G1.
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PMID:Inactivation of a Cdk2 inhibitor during interleukin 2-induced proliferation of human T lymphocytes. 751 74

Transforming growth factor beta 1 (TGF beta 1) is a cytokine capable of inhibiting or stimulating cell growth, depending on the nature of the target cell. Inhibition of cell growth by TGF beta 1 is thought to be mediated by TGF beta 1-induced changes in the expression and activity of cell cycle regulatory proteins like cyclin-dependent kinase (cdk) 2 and cdk4. Here we show that adenovirus E1A blocks growth inhibition by TGF beta 1. The activity of cdk2 was strongly inhibited by TGF beta 1 in control cells but not in E1A-expressing cells. Similarly, an early event in TGF beta 1 signaling, junB induction, was significantly reduced in E1A-expressing cells. E1A also interferes with growth stimulation of NRK cells by TGF beta 1, both in monolayer and in soft agar. In these cells, E1A also interferes with junB induction by TGF beta 1. Moreover, E1A abrogates TGF beta 1-induced production of an autocrine-acting platelet-derived growth factor-like activity. These results show that E1A can interfere with TGF beta 1-induced growth-inhibiting as well as growth-promoting signals.
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PMID:Adenovirus E1A antagonizes both negative and positive growth signals elicited by transforming growth factor beta 1. 764 36

G1 progression in mammalian cells requires the activity of the cyclin D-dependent kinases Cdk4 and/or Cdk6 and the cyclin E-dependent kinase Cdk2. Proliferating Mv1Lu mink lung epithelial cells and human keratinocytes contain high levels of the universal Cdk inhibitor p27Kip1 distributed in complexes with Cdk2, Cdk4, and Cdk6. Addition of the antimitogenic cytokine transforming growth factor-beta (TGF-beta) elevates expression of the Cdk4/6-specific inhibitor p15Ink4B and induces the release of p27 from Cdk4 and Cdk6. In Mv1Lu cells, this release of p27 coincides with increased binding of p27 to Cdk2. Recombinant p15 inhibits p27 binding to Cdk4 in vitro, and p15 overexpression induces the transfer of p27 from Cdk4 to Cdk2 in vivo, suggesting that the release of Cdk4-bound p27 in TGF-beta-treated cells is caused by the surge in p15 levels. In keratinocytes, TGF-beta increases not only p15 but also p21Cip1, which binds to Cdk2. These events correlate with Cdk2 inhibition and cell cycle arrest and occur without a loss of G1 Cdk components. The results suggest that TGF-beta induces G1 arrest in these two epithelial cell types by inhibiting various cyclin-Cdk kinases through the cooperative action of an Ink4 Cdk inhibitor and a Cip/Kip Cdk inhibitor. Subsequent to cell cycle arrest, Cdk2 and Cdk4 levels decline as part of a second set of events that may represent a program of cell adaptation to the quiescent state.
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PMID:Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. 764 71

Even though the "low-risk" human papillomavirus (HPV) diseases, such as condyloma acuminatum, rarely progress to malignancy, their high incidence evidences the need for a better understanding of molecular interactions between these viruses and the epithelium. Our study examined the contribution of altered expression of certain cytokines and antioncogenes to the hyperproliferative properties of HPV-related skin lesions. The "low-risk" human papillomavirus types (HPV 6 or 11) were determined by in situ hybridization and PCR amplification followed by direct sequencing using consensus primers from the highly conserved L1 region in six different condylomas. mRNA levels of certain cytokines (e.g., TGF-beta 1, IFN-beta), tumor suppressor genes (RB, p53), c-myc, epidermal growth factor receptor, and cdc2 kinase were measured by RT/PCR. A characteristic change in mRNA levels of those genes was found in condylomas compared to that of the expression levels of uninfected skin. Western blot experiments demonstrated a higher proportion of the hyperphosphorylated form of RB protein and a higher level of cdc2 kinase and c-myc, but low p53 and TGF-beta 1 levels in condylomas. These data reflect a higher proliferative state of those condylomas compared to the normal skin, suggesting a direct or indirect involvement of "low-risk" HPVs in interaction with the cellular cytokine/antioncogene system providing growth advantage to those infected cells.
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PMID:Alterations in cytokine/antioncogene expression in skin lesions caused by "low-risk" types of human papillomaviruses. 816 33

Rapamycin (Sirolimus, Rapamune), a potent immunosuppressive agent, has been demonstrated to have remarkable activity in inhibiting allograft rejection in animal models of transplantation. It is currently in phase II clinical trials. Rapamycin belongs to the class of macrocyclic immunosuppressive drugs that are bioactive only when bound to immunophilins. Cyclosporin A and FK506, two other members of this class, selectively block the transcriptional activation of several cytokine genes, thereby inhibiting cytokine production. Although rapamycin and its structural analog FK506 bind to the same immunophilin (FKBP), rapamycin acts at a later stage in T-cell cycle progression by blocking cytokine-mediated signal transduction pathways. This inhibition is the consequence of modulation of activity of a target protein by the rapamycin: FKBP complex [sirolimus effector protein (SEP)]. Although the identification of SEP has recently been reported, its function in cell-cycle progression is not known. The biochemical events that rapamycin has been shown to inhibit are (a) activation of p70S6 kinase, (b) activation of cdk2/cyclin E complex, (c) phosphorylation of retinoblastoma protein, and (d) suppression of cdc2 and cyclin A transcription.
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PMID:Rapamune (Sirolimus, rapamycin): an overview and mechanism of action. 858 37

Rapamycin has potent immunosuppressive properties reflecting its ability to disrupt cytokine signaling that promotes lymphocyte growth and differentiation. In IL-2-stimulated T cells, rapamycin impedes progression through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Two major biochemical alterations underlie this mode of action. The first one affects the phosphorylation/activation of the p70 S6 kinase (p70s6k), an early event of cytokine-induced mitogenic response. By inhibiting this enzyme, whose major substrate is the 40S ribosomal subunit S6 protein, rapamycin reduces the translation of certain mRNA encoding for ribosomal proteins and elongation factors, thereby decreasing protein synthesis. A second, later effect of rapamycin in IL-2-stimulated T cells is an inhibition of the enzymatic activity of the cyclin-dependent kinase cdk2-cyclin E complex, which functions as a crucial regulator of G1/S transition. This inhibition results from a prevention of the decline of the p27 cdk inhibitor, that normally follows IL-2 stimulation. To mediate these biochemical alterations, rapamycin needs to bind to intracellular proteins, termed FKBP, thereby forming a unique effector molecular complex. However, neither(p70s6k) inhibition, nor p27-induced cdk2-cyclin E inhibition are directly caused by the FKBP-rapamycin complex. Instead, this complex physically interacts with a novel protein, designated "mammalian target of rapamycin" (mTOR), which has sequence homology with the catalytic domain of phosphatidylinositol kinases and may therefore be itself a kinase. mTOR may act upstream of (p70s6K) and cdk2-cyclin E in a linear or bifurcated pathway of growth regulation. Molecular dissection of this pathway should further unravel cytokine-mediated signaling processes and help devise new immunosuppressants.
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PMID:Mechanism of action of the immunosuppressant rapamycin. 859 3

Alpha interferon is a potent growth inhibitor of Daudi Burkitt's lymphoma cells. We show here that alpha-interferon signaling interacted simultaneously with several components of the basic cell cycle machinery, causing cells to enter into a state that had many features characteristic of the G0 state. Within a few hours after alpha-interferon treatment, cyclin D3 mRNA and protein levels dropped to undetectable levels and, in parallel, the activities of cyclin A- and cyclin E-associated kinases were significantly reduced. The latter resulted from the rapid alpha-interferon-mediated elimination of cdc25A, a phosphatase that is required for antagonism of negative tyrosine phosphorylation of cdk2 in cyclin-cdk complexes. This regulation represents a novel mechanism through which an external inhibitory cytokine interacts with the cell cycle machinery. At later time points after alpha-interferon treatment, the levels of the 55-kDa slowly migrating hyperphosphorylated form of cyclin E and of cyclin A were also reduced. The antiproliferative effects were reversible, and cultures from which alpha interferon was removed reentered S phase after a lag that typically corresponded to approximately two doubling times. During this lag period, the expression of cyclin D3 and cyclin A, as well as of the cdc25A phosphatase, continued to be switched off, in spite of the removal of alpha interferon from the cell surface. In contrast, c-myc, which represents another downstream target gene that is subjected to negative regulation by alpha interferon, was relieved from suppression much earlier, concomitant with the decay in early signaling of the cytokine. The delayed pattern of cyclin reexpression provides evidence that alpha-interferon signaling imposes a G0-like state on this system.
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PMID:Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest. 866 11

Progression through the cell cycle is a tightly controlled process that integrates signals generated at the plasma membrane with the proteins that form the cell cycle machinery. The current study chronicles the induction of cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors in low density primary mouse B lymphocytes after anti-immunoglobulin plus interleukin 4 (IgM + IL-4) stimulation. In this system, > 85% of cells remain in the G0/G1 phase of cell cycle for an initial 24-h period, followed by entry of up to 50% of the cells into S phase, commencing around 30 h and peaking at 48 h. Extensive time course analyses of these anti-IgM + IL-4-stimulated B cells revealed that the G1-associated D-type cyclins D2 and D3 were induced by 3 h after stimulation, and that cyclins E, A, and B were subsequently induced sequentially, beginning at mid-G1, G1/S transition, and S phase, respectively. The G1-associated cyclin D1 was not expressed at any stage of the anti-Ig + IL-4-induced B cell cycle. cdk2, cdk4, and cdk6 were induced during G1, whereas cell division cycle-2 (cdc2) was induced concomitantly with S phase. Irrespective of their expression, the kinases cdk2 and cdc2 were only active from S phase onwards, suggesting that productive cyclin/kinase complex formation did not occur until that time. Cell cycle inhibitors p21 and p19 were induced by anti-Ig + IL-4, peaking in expression at mid-G1 and S phase, respectively. Stimulation of low density B cells with anti-Ig + IL-4 caused rapid down regulation of the p27 inhibitor, however this protein was reexpressed at 54-96 h after stimulation. In contrast, B cells stimulated with anti-CD40, a stimulus which induces long-term B cell proliferation, permanently down regulated p27. These findings are consistent with the concept that p27 reexpression contributes to the G1 arrest that follows antigen receptor crosslinking. Low density B cells cultured in the viability-enhancing cytokine IL-4 alone also showed induction of D2 and D3 cyclin expression. However, the D2 expression was transient, and the D3 expression was substantially lower than that observed in B cells induced to proliferate by anti-Ig + IL-4. This partial induction of D2 and D3 expression may explain IL-4's ability to promote B cell entry into G1 but not S phase of cell cycle, and furthermore, its ability to truncate G1 progression when B cells are subsequently stimulated with anti-Ig.
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PMID:Induction of cell cycle regulatory proteins in anti-immunoglobulin-stimulated mature B lymphocytes. 876 Jul 94

In summary, TGF-beta induces cell cycle arrest, at least in part, through down-regulation of cdk4 levels and inhibition of cdk2 activity. Thus both of the kinases thought to be responsible for phosphorylation and inactivation of RB in mid to late G1 are affected by the cytokine. Inhibition of cdk4 synthesis occurs at the translational level, is p53 dependent, and requires the 5' UTR of cdk4. David Beach's laboratory has found that TGF-beta also causes the induction of the cdk4-specific inhibitor p15 (a p16 family member). Thus TGF-beta uses two pathways to regulate cdk4 function: decreasing its expression and inhibiting its function. Mutant p53 confers resistance to TGF-beta by preventing cdk4 down-regulation and overcoming the inhibition of cdk2 activity. Work from the laboratories of both Massague and Roberts has shown that the inhibition of cdk2 brought about by TGF-beta is caused by the cdk inhibitor p27.
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PMID:p53-dependent repression of cdk4 synthesis in transforming growth factor-beta-induced G1 cell cycle arrest. 883 83


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