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

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a well-known chemical carcinogen that is widely used for animal carcinogenesis model. Treatment of MNNG, through drinking-water, can evoke multiple tumors in gastro-intestinal tract. In addition, MNNG shows the synergic effect with infection such as H. pylori on gastric cancer formation. Although tumorigenic ability of MNNG is known to be related with DNA alkylation, however, recent reports suggested that MNNG-induced tumors do not show the difference in DNA methylation, and genetic mutation profile is quite different from similar DNA alkylating agent, MNU-inducing cancer. Otherwise, genetic mutation of Ras is frequently detected in MNNG-induced tumors. Considering them, tumorigenic property of MNNG would be related with Ras. So we checked the effect of MNNG on Ras pathway. In this study, we demonstrated that MNNG could activate Ras-MAPK pathway as oncogenic Ras dependent manner. Activation of Erk by MNNG could not suppressed by cycloheximide and ALLN. In addition, Inhibition of PI3K, p38/HOG1, Raf, and CDK could not block the MNNG-induced p-Erk activation, whereas U0126 and PD98059 abolished it. Moreover, MNNG could reduce the expression of E-cadherin and promote dissociation of beta-catenin from E-cadherin through oncogenic-Ras-MAPK pathway. These results strongly suggested that oncogenic Ras would be direct target of MNNG and provided new insight that carcinogen also possesses it specific target.
 ...
PMID:Chemical carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine, is a specific activator of oncogenic Ras. 1749 35

The growth factor hepatocyte growth factor (HGF), also known as scatter factor, and its tyrosine kinase receptor c-Met play important roles in medulloblastoma malignancy. The transcription factor c-Myc is another contributor to the malignancy of these most common pediatric brain tumors. In the present study, we observed strong morphological similarities between medulloblastoma xenografts overexpressing HGF and medulloblastoma xenografts overexpressing c-Myc. We therefore hypothesized a biologically significant link between HGF/c-Met and c-Myc in medulloblastoma malignancy and studied the molecular and functional interactions between them. We found that HGF induces c-Myc mRNA and protein in established and primary medulloblastoma cells. HGF regulated c-Myc levels via transcriptional and post-transcriptional mechanisms as evidenced by HGF induction of c-Myc promoter activity and induction of c-Myc protein levels in the setting of inhibited transcription and translation. We also found that HGF induces cell cycle progression, cell proliferation, apoptosis and increase in cell size in a c-Myc-dependent manner. Activation of MAPK and PI3K, inhibition of GSK-3beta and translocation of beta-catenin to the nucleus as well as Tcf/Lef transcriptional activity were involved in mediating c-Myc induction by HGF. Induction of Cdk2 kinase activity was involved in mediating the cell cycle progression effects, and downregulation of Bcl-XL was involved in mediating the proapoptotic effects of HGF downstream of c-Myc. All molecules that mediated the effects of HGF on c-Myc expression, cell proliferation and apoptosis were expressed in human large-cell medulloblastoma tissues. We therefore established for the first time a functional cooperation between HGF/c-Met and c-Myc in human medulloblastoma and elucidated the molecular mechanisms of this cooperation. The findings provide a potential explanation for the high frequency of c-Myc overexpression in medulloblastoma and suggest a cooperative role for c-Met and c-Myc in large-cell anaplastic medulloblastoma formation.
 ...
PMID:Functional and molecular interactions between the HGF/c-Met pathway and c-Myc in large-cell medulloblastoma. 1805 65

The deposition of highly phosphorylated microtubule-associated tau protein has been observed in ALS with cognitive impairment (ALSci). In these studies, we have examined whether the expression of two candidate protein kinases for mediating tau hyperphosphorylation (GSK3beta or CDK5) are also altered. The expression of GSK, CDK and p25/p35 was assayed in human frontal, hippocampal, cerebellar, cervical (dorsal and ventral) and lumbar (dorsal and ventral) tissue from neurologically intact control (5), ALS (5) or ALSci (5) patients using RT-PCR, Western blot or immunohistochemistry. To assess GSK-3beta activity, we examined GSK3beta, phospho-GSK3beta and phospho-beta-catenin expression. Expression levels relative to that of beta-actin were compared by ANOVA. The expression of GSK, GSK3beta and phospho-GSK3beta was increased in both ALS and ALSci compared to that of the control. This was accompanied by an increased expression of phospho-beta-catenin. No significant difference between control, ALS or ALSci was observed with respect to the expression of CDK5 or p25/p35. Both GSK3beta and phospho-GSK3beta immunoreactive neurons were mainly located in layer II and layer III in the frontal cortex and in layer II in the hippocampus. This was consistent with the previously described distribution of hyperphosphorylated tau bearing neurons in ALS and ALSci. These data suggest that GSK3beta expression is upregulated in ALS and ALSci and that GSK3beta activation is associated with the intraneuronal deposition of hyperphosphorylated tau protein. This supports the potential role for GSK3beta as a therapeutic target in ALS.
 ...
PMID:Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). 1822 34

Mel-18, a polycomb group (PcG) protein, has been suggested as a tumor suppressor in human breast cancer. Previously, we reported that Mel-18 has antiproliferative activity in breast cancer cells. However, its functional mechanism has not been fully elucidated. Here, we investigated the role of Mel-18 in human breast cancer. We saw an inverse correlation between Mel-18 and phospho-Akt, which were expressed at low and high levels, respectively, in primary breast tumor tissues from 40 breast cancer patients. The effect of Mel-18 on cell growth was examined in two breast cancer cell lines, SK-BR-3 and T-47D, which express relatively low and high levels of endogenous Mel-18, respectively. On Mel-18 overexpression in SK-BR-3 cells, cell growth was attenuated and G(1) arrest was observed. Likewise, suppression of Mel-18 by antisense expression in T-47D cells led to enhanced cell growth and accelerated G(1)-S phase transition. In these cells, cyclin-dependent kinase (Cdk)-4 and Cdk2 activities were affected by Mel-18, which were mediated by changes in cyclin D1 expression and p27(Kip1) phosphorylation at Thr(157), but not by INK4a/ARF genes. The changes were both dependent on the phosphatidylinositol 3-kinase/Akt signaling pathway. Akt phosphorylation at Ser(473) was reduced by Mel-18 overexpression in SK-BR-3 cells and enhanced by Mel-18 suppression in T-47D cells. Akt-mediated cytoplasmic localization of p27(Kip1) was inhibited by Mel-18 in SK-BR-3 cells. Moreover, Mel-18 overexpression showed reduced glycogen synthase kinase-3beta phosphorylation, beta-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level. Taken together, we established a linear relationship between Mel-18-->Akt-->G(1) phase regulators.
 ...
PMID:Mel-18 negatively regulates INK4a/ARF-independent cell cycle progression via Akt inactivation in breast cancer. 1851 79

The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2) transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, alpha smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and beta-catenin and p120(ctn) localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, beta-catenin, and p120(ctn) to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers.
 ...
PMID:Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component. 1895 33

Thyroid hormone action, widely recognized on cell proliferation and metabolism, has recently been related to the phosphoinositide 3 kinase (PI3K), an upstream regulator of the Akt kinase and the involvement of the thyroid hormone receptor beta1 has been hypothesized. The serine-threonine kinase Akt can regulate various substrates that drive cell mass proliferation and survival. Its action has also been characterized in pancreatic beta-cells. We previously demonstrated that Akt activity and its activation in the insulinoma cell line hCM could be considered a specific target of the non-genomic action of T3. In this study we analyzed the molecular pathways involved in the regulation of cell proliferation, survival, size, and protein synthesis by T3 in a stable TRbeta1 interfered insulinoma cell line, derived from the hCM, and evidenced a strong regulation of both physiological and molecular events by T3 mediated by the thyroid hormone receptor beta1. We showed that the thyroid receptor beta1 mediates the T3 regulation of the cdk4.cyc D1.p21(CIP1).p27(KIP1) complex formation and activity. In addition TRbeta1 is essential for the T3 upregulation of the Akt targets beta-catenin, p70S6K, and for the phosphorylation of Bad and mTOR. We demonstrated that the beta1 receptor mediates the T3 upregulation of protein synthesis and cell size, together with the cell proliferation and survival, playing a crucial role in the T3 regulation of the PI3K/Akt pathway.
 ...
PMID:The TRbeta1 is essential in mediating T3 action on Akt pathway in human pancreatic insulinoma cells. 1916 Apr 3

1. The Wnt/beta-catenin pathway plays a critical role in carcinogenesis and so agents that target Wnt/beta-catenin may have potential in cancer prevention and therapy. The aim of the present study was to evaluate the anticancer activity of the novel natural product dammarane-type triterpene sapogenin (20(S)-25-OCH3-PPD; PPD25) isolated from the leaves of Panax notoginseng. 2. The anticancer activity of PPD25 was evaluated in three colon cancer cell lines and in one lung cancer cell line. The effects of PPD25 to inhibit proliferation and to induce apoptosis were evaluated. In addition, the potential mechanisms underlying the effects of PPD25 were investigated. 3. It was found that the addition of 5 or 25 micromol/L PPD25 to the culture medium significantly inhibited cell proliferation and induced apoptosis in all four cancer cell lines. Mechanistic studies revealed that PPD25 significantly reduced the expression of beta-catenin, a key mediator in the Wnt pathway, as well as transcriptional targets of beta-catenin, namely c-myc, cyclin D1, cdk4 and T cell factor (TCF)-4. In addition, beta-catenin/TCF transcriptional activity was significantly suppressed by PPD25. 4. The data demonstrate that the PPD25 exerts its anticancer effect by targetting beta-catenin signalling, suggesting that PPD25 may have potential as a chemotherapeutic and/or chemopreventive agent for colon and lung cancer.
 ...
PMID:Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: Targetting beta-catenin signalling. 1941 87

Schlafen-3 (Slfn-3), a novel gene, has been shown to be a negative regulator of proliferation. The current investigation was undertaken to determine whether Slfn-3 might play a role in regulating cellular differentiation. Butyric acid, a short chain fatty acid, which induced differentiation of intestinal cells as evidenced by increased alkaline phosphatase (ALP) activity in the rat small intestinal IEC-6 cells, also produced a marked increase in Slfn-3 expression. Furthermore, overexpression of Slfn-3 caused stimulation of ALP activity in IEC-6 cells, which was exacerbated by butyrate. On the other hand, downregulation of Slfn-3 by slfn-3-si-RNA greatly attenuated the butyrate-mediated induction of differentiation of IEC-6 cells. Additionally, we observed that increased expression of Slfn-3 in colon cancer HCT-116 cells stimulated TGF-beta expression and modulated expression of its downstream effectors as evidenced by increased expression of p27kip1 and downregulation of CDK-2. In addition, Slfn-3 increases E-cadherin expression but downregulates beta-catenin. In conclusion, our data show that Slfn-3 plays a critical role in regulating intestinal mucosal differentiation. Furthermore our data also show that TGF-beta signaling pathway plays an important role in mediating slfn-3 induced differentiation.
 ...
PMID:Schlafen-3: a novel regulator of intestinal differentiation. 1970 12

Mutations in adenomatous polyposis coli (APC) protein is a major contributor to tumor initiation and progression in several tumor types. These mutations affect APC function in the Wnt-beta-catenin signaling and influence mitotic spindle anchoring to the cell cortex and orientation. Here we report that the mitotic anchoring and orientation function of APC is regulated by cyclin A/cdk2. Knockdown of cyclin A and inhibition of cdk2 resulted in cells arrested in mitosis with activation of the spindle assembly checkpoint. The mitotic spindle was unable to form stable attachments to the cell cortex, and this resulted in the spindles failing to locate to the central position in the cells and undergo dramatic rotation. We have demonstrated that cyclin A/cdk2 specifically associates with APC in late G2 phase and phosphorylates it at Ser-1360, located in the mutation cluster region of APC. Mutation of APC Ser-1360 to Ala results in identical off-centered mitotic spindles. Thus, this cyclin A/cdk2-dependent phosphorylation of APC affects astral microtubule attachment to the cortical surface in mitosis.
 ...
PMID:Cyclin A/cdk2 regulates adenomatous polyposis coli-dependent mitotic spindle anchoring. 1970 5

Pituitary tumours are benign neoplasms that may cause major endocrine dysfunction. Transgenic disruption of the cell cycle machinery frequently leads to pituitary adenoma formation in animal models. The molecular analysis of human pituitary tumours has found various alterations in the expression of cell cycle regulators: cyclins, cyclin-dependent kinases and their inhibitors. There are also different mechanisms (e.g. hypermethylation, frameshift mutations, increased proteasome degradation) responsible for changed expression in cyclin mRNA and protein. It is probable that the primary initiating events lie beyond the cell cycle and may be related to co-activation of Akt, MAP-kinase and beta-catenin pathways. Nevertheless, molecular CDK inhibitors may play a role in pituitary tumour treatment in the future.
 ...
PMID:Cyclins and their related proteins in pituitary tumourigenesis. 2034 31


<< Previous 1 2