Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Nuclear Factor (NF)-kappaB family of transcription factors controls expression of genes which promote cell growth, survival, and neoplastic transformation. Recently we demonstrated aberrant constitutive activation of NF-kappaB in primary human and rat breast cancer specimens and in cell lines. Overexpression of the epidermal growth factor receptor (EGFR) family member Her-2/neu, seen in approximately 30% of breast cancers, is associated with poor prognosis. Previously, Her-2/neu has been shown to signal via a phosphatidylinositol 3 (PI3)-kinase to Akt/protein kinase B (PKB) pathway. Since this signaling pathway was recently shown to activate NF-kappaB, here we have tested the hypothesis that Her-2/neu can activate NF-kappaB in breast cancer. Overexpression of Her-2/neu and EGFR-4 in Ba/F3 cells led to constitutive PI3- and Akt kinase activities, and induction of classical NF-kappaB (p50/p65). Similarly, a tumor cell line and tumors derived from MMTV-Her-2/neu transgenic mice displayed elevated levels of classical NF-kappaB. Engagement of Her-2/neu receptor downregulated the level of NF-kappaB. NF-kappaB binding and activity in the cultured cells was reduced upon inhibition of the PI3- to Akt kinase signaling pathway via ectopic expression of kinase inactive mutants, incubation with wortmannin, or expression of the tumor suppressor phosphatase PTEN. Inhibitors of calpain, but not the proteasome, blocked IkappaB-alpha degradation. Inhibition of Akt did not affect IKK activity. These results indicate that Her-2/neu activates NF-kappaB via a PI3- to Akt kinase signaling pathway that can be inhibited via the tumor suppressor PTEN, and is mediated by calpain rather than the IkappaB kinase complex.
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PMID:Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN. 1131 73

We have shown that TGF-beta plays an important role during the period of developmental cell death in the nervous system. Immunoneutralization of TGF-beta prevents ontogenetic neuron death in vivo. Like neurons, oligodendrocytes are generated in excess and eliminated by apoptosis. It has been shown that oligodendrocyte progenitors and newly formed oligodendrocytes are especially susceptible to apoptosis. We choose the oligodendrocyte precursor cell line OLI-neu to address the question if TGF-beta could play a role for the control of oligodendrocyte proliferation and cell death. Flow cytometric analysis revealed that OLI-neu cells arrested in the G1 phase of the cell cycle underwent apoptosis in response to TGF-beta. TUNEL assays, apoptosis ELISA, and caspase assays substantiated the finding that OLI-neu cells died after TGF-beta treatment. Cell death could be inhibited by application of pan-caspase or caspase 8 and 9 inhibitors, whereas the inhibition of calpain was unaffected. Furthermore, we found a reduction of bcl-X(L) at the protein as well as at the mRNA level, while p27 was upregulated. The Smad cascade was activated while TGF-beta reduced the activity of the p42/p44 MAP kinase pathway. Together, these data show that TGF-beta induced apoptotic cell death in cells of oligodendroglial origin, whereby the signaling cascade involved the downregulation of antiapoptotic signaling such as bcl-X(L) leading to the activation of caspases.
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PMID:TGF-beta induces cell death in the oligodendroglial cell line OLI-neu. 1223 47

The Her-2/neu oncogene, the second member of the epidermal growth factor (EGF) receptor family, encodes a transmembrane tyrosine kinase receptor. Overexpression of Her-2/neu in approximately 30% of breast cancers is associated with poor overall survival. Recently, we have found that Her-2/neu activates nuclear factor (NF)-kappaB via a phosphatidylinositol 3 kinase (PI3-K)-Akt kinase signaling pathway in mouse mammary tumor virus (MMTV)-Her-2/neu NF639 mouse breast cancer cells. Surprisingly, the IkappaB kinase (IKK) kinase complex, implicated in proteasome-mediated degradation of IkappaB-alpha and activation of NF-kappaB via the canonical pathway, was not activated in these cells. Degradation of IkappaB-alpha was mediated via calpain, which in B cells is facilitated by phosphorylation of IkappaB-alpha by the protein kinase CK2. Here, we report that the inhibition of CK2 blocks Her-2/neu-mediated activation of NF-kappaB. NF639 breast cancer cells, stably expressing CK2alpha or CK2alpha' kinase-inactive mutants, displayed decreased NF-kappaB binding and reduced ability to grow in soft agar, as well as increased sensitivity to tumor necrosis factor (TNF)-alpha killing. Similarly, CK2 kinase-inactive subunits inhibited NF-kappaB activity in Hs578T human breast cancer cells, which also display elevated CK2 activity. In NIH 3T3 fibroblasts, which express low basal NF-kappaB and CK2 activities, overexpression of CK2 by retroviral gene delivery led to increased IkappaB-alpha turnover and the induction of classical NF-kappaB (p50/RelA). Thus, CK2 plays an important role in Her-2/neu signaling, promoting IkappaB-alpha degradation and, thereby, NF-kappaB activation. Furthermore, because ectopic CK2 activity appears sufficient to induce NF-kappaB, the elevated CK2 activity observed in many primary human breast cancers likely plays a role in aberrant activation of NF-kappaB and, therefore, represents a potential therapeutic target.
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PMID:Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. 1243 79