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)

We examined the potential role of SMAD7 in human epidermal keratinocyte differentiation. Overexpression of SMAD7 inhibited the activity of the proliferation-specific promoters for the keratin 14 and cdc2 genes and reduced the expression of the mRNA for the proliferation-specific genes cdc2 and E2F1. The ability of SMAD7 to suppress cdc2 promoter activity was lost in transformed keratinocyte cell lines and was mediated by a domain(s) located between aa 195-395 of SMAD7. This domain lies outside the domain required to inhibit TGFbeta1 signaling, suggesting that this activity is mediated by a novel functional domain(s). Examination of AP1, NFkappaB, serum response element, Gli, wnt, and E2F responsive reporters indicated that SMAD7 significantly suppressed the E2F responsive reporter and modestly increased AP1 activity in proliferating keratinocytes. These data suggest that SMAD7 may have a role in TGFbeta-independent signaling events in proliferating/undifferentiated keratinocytes. The effects of SMAD7 in differentiated keratinocytes indicated a more traditional role for SMAD7 as an inhibitor of TGFbeta action. SMAD7 was unable to initiate the expression of differentiation markers but was able to superinduce/derepress differentiation-specific markers and genes in differentiated keratinocytes. This latter role is consistent with the ability of SMAD7 to inhibit TGFbeta-mediated suppression of keratinocyte differentiation and suggest that the opposing actions of SMAD7 and TGFbeta may serve to modulate squamous differentiation.
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PMID:Modulation of proliferation-specific and differentiation-specific markers in human keratinocytes by SMAD7. 1502 26

Induction of G(1) arrest by TGF-beta correlates with the regulation of p21(Cip1) and p27(Kip1), members of the Cip/Kip family of cyclin-dependent kinase inhibitors (cki). However, no definitive evidence exists that these proteins play a causal role in TGF-beta(1)-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF-beta is diminished in T cells from mice deficient for both p21(Cip1) and p27(Kip1) (double-knockout (DKO)) only when activated under conditions of optimal costimulation. Although there is an IL-2-dependent enhanced proliferation of CD8(+) T cells from DKO mice, TGF-beta is able to maximally suppress the proliferation of DKO T cells when activated under conditions of low costimulatory strength. We also show that the induction of p15(Ink4b) in T cells stimulated in the presence of TGF-beta is not essential, as TGF-beta also efficiently suppressed proliferation of T cells from p15(Ink4b-/-) mice. Finally, although these cki are dispensable for the suppression of T cell proliferation by TGF-beta, we now describe a Smad3-dependent down-regulation of cdk4, suggesting a potential mechanism underlying to resistance of Smad3(-/-) T cells to the induction of growth arrest by TGF-beta. In summary, the growth suppressive effects of TGF-beta in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF-beta by lowering thresholds for a maximal mitogenic response.
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PMID:p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness. 1532 69

Keratinocyte growth factor (KGF) is a mitogen for rat type II cells and also stimulates differentiation in vitro. Administration of KGF also protects the lung from a variety of injuries and subsequent development of fibrosis. Because transforming growth factor (TGF)-beta has been shown to inhibit epithelial cell proliferation and surfactant protein gene expression in other systems and is thought to be a major effector in pulmonary fibrosis, we sought to determine if TGF-beta would antagonize the effects of KGF in primary cultures of alveolar type II cells. Type II cells were cultured on a matrix of type I collagen and Matrigel in the presence or absence of KGF and/or TGF-beta. KGF alone greatly stimulated proliferation and increased cyclin-dependent kinase (cdk) 2 kinase activity and Retinoblastoma susceptibility gene product (Rb) phosphorylation. Cyclin D1, cdk2, and cdc25A protein levels were increased, and p15(Ink4b) and p27(Kip1) protein levels were decreased. TGF-beta markedly inhibited alveolar epithelial cell proliferation induced by KGF. TGF-beta inhibited cdk2 enzyme activity and Rb phosphorylation and increased p15(Ink4b) protein levels. TGF-beta also inhibited differentiation induced by KGF as measured by secretion of surfactant protein-A into the apical media. In summary, TGF-beta inhibits the proliferative effect of KGF in vitro and may be a biologic antagonist of KGF.
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PMID:Transforming growth factor-beta antagonizes alveolar type II cell proliferation induced by keratinocyte growth factor. 1533 29

Cyclin D1 is frequently overexpressed in human breast cancers, and cyclin D1 overexpression correlates with poor prognosis. Cyclin D1-Cdk2 complexes were previously observed in human breast cancer cell lines, but their role in cell cycle regulation and transformation was not investigated. This report demonstrates that Cdk2 in cyclin D1-Cdk2 complexes from mammary epithelial cells is phosphorylated on the activating phosphorylation site, Thr(160). Furthermore, cyclin D1-Cdk2 complexes catalyze Rb phosphorylation on multiple sites in vitro. As a model to investigate the biological and biochemical functions of cyclin D1-Cdk2 complexes, and the mechanisms by which cyclin D1 activates Cdk2, a cyclin D1-Cdk2 fusion gene was constructed. The cyclin D1-Cdk2 fusion protein expressed in epithelial cells was phosphorylated on Thr(160) and catalyzed the phosphorylation of Rb on multiple sites in vitro and in vivo. Kinase activity was not observed if either the cyclin D1 or Cdk2 domain was mutationally inactivated. Mutational inactivation of the cyclin D1 domain prevented activating phosphorylation of the Cdk2 domain on Thr(160). These results indicate that the cyclin D1 domain of the fusion protein activated the Cdk2 domain through an intramolecular mechanism. Cells stably expressing the cyclin D1-Cdk2 fusion protein exhibited several hallmarks of transformation including hyperphosphorylation of Rb, resistance to TGFbeta-induced growth arrest, and anchorage-independent proliferation in soft agar. We propose that cyclin D1-Cdk2 complexes mediate some of the transforming effects of cyclin D1 and demonstrate that the cyclin D1-Cdk2 fusion protein is a useful model to investigate the biological functions of cyclin D1-Cdk2 complexes.
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PMID:Construction of a cyclin D1-Cdk2 fusion protein to model the biological functions of cyclin D1-Cdk2 complexes. 1535 84

Fibroblast proliferation, differentiation, and migration contribute to the characteristic pulmonary vascular remodeling seen in primary pulmonary hypertension (PPH). The identification of mutations in the bone morphogenetic protein type II receptor (BMPRII) in PPH have led us to question what role BMPRII and its ligands play in pulmonary vascular remodeling. Thus, to further understand the functional significance of BMPRII in the pulmonary vasculature, we examined the expression of TGF-beta superfamily receptors in human fetal lung fibroblasts (HFL) and investigated the role of BMP4 on cell cycle regulation, fibroblast proliferation, and differentiation. Furthermore, signaling pathways involved in these processes were examined. HFL expressed BMPRI and BMPRII mRNA and demonstrated specific I(125)-BMP4 binding sites. BMP4 inhibited [(3)H]thymidine incorporation and proliferation of HFL; protein expression was increased for the cell cycle inhibitor p21 and reduced for the positive regulators cyclin D and cdk2 by BMP4. BMP4 induced differentiation of HFL into a smooth muscle cell phenotype since protein expression of alpha-smooth muscle actin and smooth muscle myosin was increased. Furthermore, p38(MAPK), ERK1/2, JNK, and Smad1 were phosphorylated by BMP4. Using specific MAPK inhibitors, a dominant negative Smad1 construct, and Smad1 siRNA, we found that the antiproliferative and prodifferentiation effects of BMP4 were Smad1 dependent with JNK also contributing to differentiation. Because failure of Smad phosphorylation is a major feature of BMPRII mutations, these results imply that BMPRII mutations may promote the expansion of fibroblasts resistant to the antiproliferative, prodifferentiation effects of BMPs and suggest a mechanism for the vascular obliteration seen in familial PPH.
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PMID:BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. 1551 92

Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification and decreased bone mineral density in caspase-3-deficient (Casp3(-/-) and Casp3(+/-)) mice due to an attenuated osteogenic differentiation of bone marrow stromal stem cells (BMSSCs). The mechanism involved in the impaired differentiation of BMSSCs is due, at least partially, to the overactivated TGF-beta/Smad2 signaling pathway and the upregulated expressions of p53 and p21 along with the downregulated expressions of Cdk2 and Cdc2, and ultimately increased replicative senescence. In addition, the overactivated TGF-beta/Smad2 signaling may result in the compromised Runx2/Cbfa1 expression in preosteoblasts. Furthermore, we demonstrate that caspase-3 inhibitor, a potential agent for clinical treatment of human diseases, caused accelerated bone loss in ovariectomized mice, which is also associated with the overactivated TGF-beta/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-beta/Smad2 pathway and cell cycle progression.
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PMID:A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells. 1559 95

Rb family members were the only demonstrated substrates of CDK4 until it was shown recently that Smad3, which plays a key role in mediating TGF-beta antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. The Rb pathway is disrupted in almost all human cancers. Most cancers contain high levels of CDK activity due to frequent inactivation of the p16 tumor suppressor or overexpression of cyclin D1. Therefore, disruption of the Rb pathway not only inactivates Rb, but also likely diminishes Smad activity, which may contribute to tumorigenesis and resistance to the TGF-beta growth-inhibitory effects in cancers. Although genetic mutation of Smad3 has not been reported, CDK phosphorylation of Smad3 may provide an epigenetic mechanism for inhibition of the tumor suppressive function of Smad3 during the early stages of tumorigenesis.
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PMID:Inhibition of Smad antiproliferative function by CDK phosphorylation. 1561 45

Smad7 is overexpressed in 50% of human pancreatic cancers. COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-beta1 (TGF-beta1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression. To delineate the mechanisms underlying these divergent consequences of Smad7 overexpression, we studied the effects of Smad7 on TGF-beta1-dependent signaling pathways and cell cycle regulating proteins. TGF-beta1 induced the phosphorylation of MAPK, p38 MAPK, and AKT2 irrespective of the levels of Smad7, and inhibitors of these pathways did not alter TGF-beta1 actions on cell growth. By contrast, Smad7 overexpression interfered with TGF-beta1-mediated attenuation of cyclin A and B levels, inhibition of cdc2 dephosphorylation and CDK2 inactivation, up-regulation of p27, and the maintenance of the retinoblastoma protein (RB) in a hypophosphorylated state. Smad7 also suppressed TGF-beta1-mediated inhibition of E2F activity but did not alter TGF-beta1-mediated phosphorylation of Smad2, the nuclear translocation of Smad2/3/4, or DNA binding of the Smad2/3/4 complex. Although Smad7 did not associate with the type I TGF-beta receptor (TbetaRI), SB-431542, an inhibitor of the kinase activity of this receptor, blocked TGF-beta1-mediated effects on Smad-2 phosphorylation. These findings point toward a novel paradigm whereby Smad7 acts to functionally inactivate RB and de-repress E2F without blocking the activation of TbetaRI and the nuclear translocation of Smad2/3, thereby allowing for TGF-beta1 to exert effects in a cancer cell that is resistant to TGF-beta1-mediated growth inhibition.
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PMID:Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein. 1581 53

Smad3, a key mediator for TGF-beta antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. Except for the Rb family members, Smad3 is the only CDK4 substrate demonstrated so far. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. Because cancer cells often contain high levels of CDK activity, inhibition of Smad activity by CDK phosphorylation may contribute to tumorigenesis and TGF-beta resistance in cancers.
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PMID:Smad3 phosphorylation by cyclin-dependent kinases. 1628 4

The mammalian forebrain subependyma contains neural stem cells and other proliferating progenitor cells. Recent studies have shown the importance of TGF-beta family members and their adaptor proteins in the inhibition of proliferation in the nervous system. Previously, we have demonstrated that TGF-beta induces phosphorylation and association of ELF (embryonic liver fodrin) with Smad3 and Smad4 resulting in nuclear translocation. Elf(-/-) mice manifest abnormal neuronal differentiation, with loss of neuroepithelial progenitor cell phenotype in the subventricular zone (SVZ) with dramatic marginal cell hyperplasia and loss of nestin expression. Here, we have analyzed the expression of cell cycle-associated proteins cdk4, mdm2, p21, and pRb family members in the brain of elf(-/-) mice to verify the role of elf in the regulation of neural precursor cells in the mammalian brain. Increased proliferation in SVZ cells of the mutant mice coincided with higher levels of cdk4 and mdm2 expression. A lesser degree of apoptosis was observed in the mutant mice compared to the wild-type control. Elf(-/-) embryos showed elevated levels of hyperphosphorylated forms of pRb, p130 and p107 and decreased level of p21 compared to the wild-type control. These results establish a critical role for elf in the development of a SVZ neuroepithelial stem cell phenotype and regulation of neuroepithelial cell proliferation, suggesting that a mutation in the elf locus renders the cells susceptible to a faster entry into S phase of cell cycle and resistance to senescence and apoptotic stimuli.
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PMID:Cell cycle deregulation and loss of stem cell phenotype in the subventricular zone of TGF-beta adaptor elf-/- mouse brain. 1688 1


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