Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ansamycin antibiotics, such as 17-allylaminogeldanamycin (17-AAG), bind to Hsp90 and regulate its function, resulting in the proteasomal degradation of a subset of signaling proteins that require Hsp90 for conformational maturation. HER2 is a very sensitive target of these drugs. Ansamycins cause RB-dependent G1 arrest that is associated with loss of D-cyclins via a PI3 kinase, Akt dependent pathway. Downregulation of D-cyclin was due, in part, to loss of Akt expression in response to drug. Moreover, in HER2 overexpressing breast cancer cells, 17-AAG caused rapid inhibition of Akt activity prior to any change in Akt protein. Ansamycins caused rapid degradation of HER2 and a concomitant loss in HER3 associated PI3 kinase activity. This led to a loss of Akt activity, dephosphorylation of Akt substrates, and loss of D-cyclin expression. Introduction into cells of a constitutively membrane bound form of PI3 kinase prevented the effects of the drug on Akt activity and D-cyclins. Thus, in breast cancer cells with high HER2, Akt activation by HER2/HER3 heterodimers is required for D-cyclin expression. In murine xenograft models, non-toxic doses of 17-AAG markedly reduced the expression of HER2 and phosphorylation of Akt and inhibited tumor growth. Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors.
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PMID:Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. 1185 Aug 35

The oncoprotein ErbB2 is endocytosis-deficient, probably due to its interaction with Heat shock protein 90. We previously demonstrated that clathrin-dependent endocytosis of ErbB2 is induced upon incubation of cells with Ansamycin derivatives, such as geldanamycin and its derivative 17-AAG. Furthermore, we have previously demonstrated that a preubiquitinated chimeric EGFR (EGFR-Ub(4)) is constitutively endocytosed in a clathrin-dependent manner. We now demonstrate that also an ErbB2-Ub(4) chimera is endocytosed constitutively and clathrin-dependently. Upon expression, the ErbB2-Ub(4) was further ubiquitinated, and by Western blotting, we demonstrated the formation of both Lys48-linked and Lys63-linked polyubiquitin chains. ErbB2-Ub(4) was constitutively internalized and eventually sorted to late endosomes and lysosomes where the fusion protein was degraded. ErbB2-Ub(4) was not cleaved prior to internalization. Interestingly, over-expression of Ubiquitin Interaction Motif-containing dominant negative fragments of the clathrin adaptor proteins epsin1 and Eps15 negatively affected endocytosis of ErbB2. Altogether, this argues that ubiquitination is sufficient to induce clathrin-mediated endocytosis and lysosomal degradation of the otherwise plasma membrane localized ErbB2. Also, it appears that C-terminal cleavage is not required for endocytosis.
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PMID:Preubiquitinated chimeric ErbB2 is constitutively endocytosed and subsequently degraded in lysosomes. 2312 13

Intraductal carcinoma (IC) is a rare salivary gland tumor with low- to intermediate-grade cytological features. It is further classified into intercalated duct type and apocrine type based on its distinct histologic and immunohistochemical expression. Conventional salivary duct carcinoma (SDC) is an aggressive carcinoma with high-grade features and is usually associated with poor prognosis. In this study, immunohistochemistry and mutation analyses (including HRAS/PIK3CA mutations, RET rearrangement, and human epidermal growth factor receptor 2 [HER2] amplification) of 9 ICs (including 3 pure ICs, 6 ICs with invasive carcinoma) and 24 conventional SDCs were performed and the results were compared. Four intercalated duct-type cases were positive for SOX10 and S100 and negative for AR; five apocrine-type cases showed opposite results. All five apocrine-type cases had cysts with relatively circumscribed tumor borders and morphologically mimicking breast low-grade ductal carcinoma in situ or papillary carcinoma. RET fusion is detected in half of the 4 intercalated duct-type IC but not in the apocrine-type or conventional SDC. HER2 amplification was only observed in conventional SDC. The monoclonal antibody (clone RBT-NRAS) against NRAS Q61R is a sensitive and specific marker used for detecting HRAS Q61R mutation in the salivary gland tumors. The apocrine-type IC had different cytological grades, distinct tumor growth patterns, and no evidence of low- to high-grade transition, suggesting that apocrine-type IC should be distinguished from apocrine SDC with an in situ component.
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PMID:Clinicopathological study of intraductal carcinoma of the salivary gland, with emphasis on the apocrine type. 3238 6

Ethanol extract (RET) of Rosa multiflora Thunb flowers and its subfractions in ethylacetate (REA) or n-butanol subfractions (RBT) were reported to have potent antioxidative and anti-inflammatory activities. In this study, we investigated if those Rosa multiflora flower (RMF) extracts prevent ultraviolet (UV)-induced biochemical damages leading to photoaging. In keratinocyte or dermal fibroblasts, RET, REA, and RBT treatments with UV irradiation significantly decreased reactive oxygen species (ROS), interleukin (IL)-6, IL-8, and matrix metalloproteinase (MMP)-1 levels through suppression of nuclear factor kappa B and mitogen-activated protein kinases. In the animal experiment, mice were orally supplemented with RET (RET group) or REA and RBT mixture (RM group) for 10 weeks, concomitantly with UV exposure. Tumor necrosis factor alpha production and MMP-13 expression were reduced in the mouse skin of RET and RM groups compared with those in the UV control (UVC) group. UV-induced IL-6 production and epidermal thickening were reduced in RM group compared with those in UVC group. Eight phenolic compounds, including quercitrin (quercetin-3-O-rhamnoside), were identified in RMF extracts. Quercitrin treatment to dermal fibroblasts significantly attenuated an increase of MMP-1 expression and a decrease of type I procollagen expression caused by UV. Collectively, RMF extracts showed protective effects from UV-induced photoaging in the skin through suppression of ROS generation, proinflammatory cytokine production, and MMP expression. Quercitrin is suggested to be one of the effective compounds.
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PMID:Rosa multiflora Thunb Flower Extract Attenuates Ultraviolet-Induced Photoaging in Skin Cells and Hairless Mice. 3272 Dec 59