Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CCNG2 gene that encodes the unconventional cyclin G2 was one of the few genes up-regulated on anti-human epidermal growth factor receptor 2 (HER2) antibody-mediated inhibition of HER2 signaling. The purpose of this study was to explore how HER2 signaling modulates cyclin G2 expression and the effect of elevated cyclin G2 on breast cancer cell growth. Treatment of breast cancer cells that overexpress HER2 (BT474, SKBr3, and MDAMB453) with the anti-HER2 antibody trastuzumab or its precursor 4D5 markedly up-regulated cyclin G2 mRNA in vitro and in vivo, as shown by real-time PCR. Immunoblot and immunofluorescence analysis with specific antibodies against cyclin G2 showed that anti-HER2 antibody significantly increased cyclin G2 protein expression and translocated the protein to the nucleus. Trastuzumab was not able to induce cyclin G2 expression in cells weakly expressing HER2 (MCF7) or in cells that had developed resistance to trastuzumab. Enforced expression of HER2 in T47D and MDAMB435 breast cancer cells reduced cyclin G2 levels. Collectively, these data suggest that HER2-mediated signaling negatively regulates cyclin G2 expression. Inhibition of phosphoinositide 3-kinase (LY294002), c-jun NH(2)-terminal kinase (SP600125), and mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K; rapamycin) increased cyclin G2 expression. In contrast, treatment with inhibitors of p38 mitogen-activated protein kinase (SB203580), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (U0126), or phospholipase Cgamma (U73122) did not affect cyclin G2 expression. Anti-HER2 antibody in combination with LY294002, rapamycin, or SP600125 induced greater cyclin G2 expression than either agent alone. Ectopic expression of cyclin G2 inhibited cyclin-dependent kinase 2 activity, Rb phosphorylation, cell cycle progression, and cellular proliferation without affecting p27(Kip1) expression. Thus, cyclin G2 expression is modulated by HER2 signaling through multiple pathways including phosphoinositide 3-kinase, c-jun NH(2)-terminal kinase, and mTOR signaling. The negative effects of cyclin G2 on cell cycle and cell proliferation, which occur without altering p27(Kip1) levels, may contribute to the ability of trastuzumab to inhibit breast cancer cell growth.
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PMID:Roles of human epidermal growth factor receptor 2, c-jun NH2-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells. 1802 71

Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest. Moreover, insulin and insulin-like growth factor-1 (IGF-1) receptor signaling strongly represses CycG2. Here we show that blockade of ER-signaling in MCF7 and T47D BC cell lines enhances the expression and nuclear localization of CycG2. Knockdown of CycG2 attenuated the cell cycle arrest response of E2-depleted and fulvestrant treated MCF7 cells. These muted responses were accompanied by sustained inhibitory phosphorylation of retinoblastoma (RB) protein, expression of cyclin D1, phospho-activation of ERK1/2 and MEK1/2 and expression of cRaf. Our work indicates that CycG2 can form complexes with CDK10, a CDK linked to modulation of RAF/MEK/MAPK signaling and tamoxifen resistance. We determined that metformin upregulates CycG2 and potentiates fulvestrant-induced CycG2 expression and cell cycle arrest. CycG2 knockdown blunts the enhanced anti-proliferative effect of metformin on fulvestrant treated cells. Meta-analysis of BC tumor microarrays indicates that CCNG2 expression is low in aggressive, poor-prognosis BC and that high CCNG2 expression correlates with longer periods of patient survival. Together these findings indicate that CycG2 contributes to signaling networks that limit BC.
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PMID:Cyclin G2 promotes cell cycle arrest in breast cancer cells responding to fulvestrant and metformin and correlates with patient survival. 2775 29

Targeting self-renewal and tumorigenicity has been proposed as a potential strategy against cancer stem cells (CSCs). Epigenetic proteins are key modulators of gene expression and cancer development contributing to regulation and maintenance of self-renewal and tumorigenicity. Here, we have screened a small-molecule epigenetic inhibitor library using 3D in vitro models in order to determine potential epigenetic targets associated with self-renewal and tumorigenicity in Canine Mammary Cancer (CMC) cells. We identified inhibition of BET proteins as a promising strategy to inhibit CMC colonies and tumorspheres formation. Low doses of (+)-JQ1 were able to downregulate important genes associated to self-renewal pathways such as WNT, NOTCH, Hedgehog, PI3K/AKT/mTOR, EGF receptor and FGF receptor in CMC tumorspheres. In addition, we observed downregulation of ZEB2, a transcription factor important for the maintenance of self-renewal in canine mammary cancer cells. Furthermore, low doses of (+)-JQ1 were not cytotoxic in CMC cells cultured in 2D in vitro models but induced G2/M cell cycle arrest accompanied by upregulation of G2/M checkpoint-associated genes including BTG2 and CCNG2. Our work indicates the BET inhibition as a new strategy for canine mammary cancers by modulating the self-renewal phenotype in tumorigenic cells such as CSCs.
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PMID:An epigenetic screening determines BET proteins as targets to suppress self-renewal and tumorigenicity in canine mammary cancer cells. 3175 45