Superantigen enhanced protection against a weak tumor-specific melanoma antigen: Implications for prophylactic vaccination against cancer

Kominsky, Scott L.; Torres, Barbara A.; Hobeika, Amy; Lake, Faith A.; Johnson, Howard M.

doi:10.1002/ijc.1551

Cited by 29 publications

(32 citation statements)

References 25 publications

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“…For example, IFN-g and IFN-a were shown to inhibit the proliferation of PC3 and DU145 prostate cancer cell lines (van Moorselaar et al, 1991). In addition, previous studies have indicated that IFNs are capable of modulating the expression of various suppressor genes and oncogenes (Hobeika et al, 1998;Kominsky et al, 2000).…”

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confidence: 99%

Gamma interferon down-regulates Fer and induces its association with inactive Stat3 in colon carcinoma cells

et al. 2002

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Gamma interferon (IFN-g) is a regulator of cell growth, which suppresses the proliferation of HT-29 colon carcinoma cells. Here we show that in HT-29 cells IFN-g transiently increased the cellular level of the tyrosine kinase Fer, whose functioning was found to be essential for the proliferation of malignant cell-lines. The transient elevation in the level of Fer, was followed by its down-regulation, an effect which was most prominent after 6 -8 h of IFN-g treatment. Up-and downregulation of Fer was paralleled by the activation and subsequent deactivation of Stat3, which is a potent oncogene and a putative substrate of the tyrosine kinase Fer. Moreover, IFN-g induced the association of Fer and Stat3 and the newly formed complex was most stable at the down-regulated states of the two proteins. Formation of the Fer/Stat3 complex was accompanied by an attenuation in cell -cycle progression and accumulation of cells in the G1 phase. Thus, Fer and Stat3 are two proliferation-promoting factors whose down-regulation could contribute to the cytostatic activity of IFN-g in colon carcinoma cells.

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confidence: 99%

Gamma interferon down-regulates Fer and induces its association with inactive Stat3 in colon carcinoma cells

et al. 2002

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“…Importantly, ErbB-2 is frequently overexpressed in carcinomas, particularly mammary and ovarian carcinomas, and is associated with a poor prognosis (8 -10). ErbB-2 antibodies (11,12) and agents such as interferon (13) or tyrosine kinase inhibitors (14) decrease the growth of ErbB-2-expressing tumor cells and also reduce the cellular level of ErbB-2 (15). In many of these instances the decreased growth provoked by the loss of ErbB-2 is due to increased apoptosis.…”

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confidence: 99%

Caspase-dependent Cleavage of ErbB-2 by Geldanamycin and Staurosporin

Tikhomirov

Carpenter

2001

Journal of Biological Chemistry

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The geldanamycin-induced degradation of ErbB-2 produces a 23-kDa carboxyl-terminal fragment, which has been isolated and subjected to amino-terminal microsequencing. The obtained sequence indicates that the amino terminus of this fragment corresponds to Gly-1126 of ErbB-2. Analysis of the residues immediately before Gly-1126 suggests that cleavage may involve caspase activity. Site-directed mutagenesis of Asp-1125 in ErbB-2 prevents geldanamycin-provoked formation of the 23-kDa fragment, consistent with the requirement of this residue for caspase-dependent cleavage in known substrates. Also, the addition of the pan-caspase inhibitor Z-VAD-FMK blocks formation of the 23-kDa ErbB-2 fragment in cells exposed to geldanamycin. Interestingly, staurosporin and curcumin are also shown to provoke the degradation of ErbB-2 with formation of the 23-kDa carboxyl-terminal fragment. The generation of this fragment by staurosporin or curcumin is likewise blocked by caspase inhibition. Caspase inhibition does not prevent accelerated degradation of the 185-kDa native ErbB-2 in geldanamycin-treated cells but does significantly prevent staurosporin-stimulated metabolic loss of ErbB-2.ErbB-2, a Type I transmembrane receptor tyrosine kinase, functions as a co-receptor by dimerizing with ligand-occupied members of the ErbB family, the EGF receptor, ErbB-3, or ErbB-4 (1-3). This heterodimerization event is considered to alter the signaling capacity and cellular responses provoked by homodimers of occupied ErbB receptors. No ligand has been identified that directly interacts with the ectodomain of ErbB-2.ErbB-2 was originally identified as the transforming oncogene neu, which contains a point mutation in the transmembrane domain that is responsible for its oncogenic potential (4). Overexpression of ErbB-2 also produces a transformed phenotype in experimental systems (5-7). Importantly, ErbB-2 is frequently overexpressed in carcinomas, particularly mammary and ovarian carcinomas, and is associated with a poor prognosis (8 -10). ErbB-2 antibodies (11, 12) and agents such as interferon (13) or tyrosine kinase inhibitors (14) decrease the growth of ErbB-2-expressing tumor cells and also reduce the cellular level of ErbB-2 (15). In many of these instances the decreased growth provoked by the loss of ErbB-2 is due to increased apoptosis. In contrast, the overexpression of ErbB-2 can prevent the induction of apoptosis (15). Hence, the growth-controlling activity of ErbB-2 is related to structural changes or alterations in its level of expression.The benzoquinoid anasamycin antibiotic geldanamycin was first isolated and described as an inhibitor of tyrosine kinase activity (16). Subsequently, geldanamycin was shown to possess tumoricidal activity toward cell lines that overexpress ErbB-2 (17). Currently geldanamycin derivatives designed to reduce toxicity are in clinical trials for certain cancer patients (18). The addition of geldanamycin to cells results in an increased rate of degradation of several protein kinases, including ErbB-2 (17), S...

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“…IFN treatment of prostate cancer cells is known to inhibit cell proliferation (Sica et al, 1994;Kominsky et al, 2000). However, it is not known whether IFNtreatment of PrSCs results in inhibition of cell growth.…”

Section: Regulation Of Androgen Receptor Levels By Interferons Z Basrmentioning

confidence: 99%

“…Both types of IFNs function through transcriptional activation of IFNactivatable genes encoding the IFN-inducible proteins that mediate the biological activities of IFNs. Importantly, treatment of human prostate cancer cell lines with the type I IFN (Sica et al, 1994) or the type II IFN (Kominsky et al, 2000) is known to inhibit cell growth. Additionally, treatment of human prostate cancer cell line PC-3 with natural IFN-beta is known to upregulate the AR protein levels (Sica et al, 1994).…”

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confidence: 99%

Androgen receptor levels are increased by interferons in human prostate stromal and epithelial cells

et al. 2005

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Proliferation of normal and malignant prostate epithelium is regulated by androgen stimulation via both the androgen receptor (AR)-positive stromal and epithelial cells. However, it is not known how AR expression is regulated in human prostate cells. We report that treatment of normal human prostate stromal cells (PrSCs) with type I IFN (alpha or beta), but not type II IFN (gamma), resulted in increased levels of AR protein. The maximal increase in AR protein levels was dependent on the dose and the duration of the IFN-alpha treatment. We found that the increase in AR protein levels was independent of de novo transcription and protein synthesis. Interestingly, the IFN-alpha treatment of PrSCs resulted in considerable nuclear accumulation of AR, stimulation of AR-mediated transcription of reporter genes, and retardation of cell proliferation. Furthermore, treatment of normal human prostate epithelial cells with IFNs (alpha, beta or gamma) also resulted in increased levels of AR protein. Together, our observations identify the androgen receptor as an IFN-regulated protein in normal human prostate stromal and epithelial cells and predict that IFN-induced levels of AR in prostate cells contribute to the regulation of androgen signaling.

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Superantigen enhanced protection against a weak tumor-specific melanoma antigen: Implications for prophylactic vaccination against cancer

Cited by 29 publications

References 25 publications

Gamma interferon down-regulates Fer and induces its association with inactive Stat3 in colon carcinoma cells

Gamma interferon down-regulates Fer and induces its association with inactive Stat3 in colon carcinoma cells

Caspase-dependent Cleavage of ErbB-2 by Geldanamycin and Staurosporin

Androgen receptor levels are increased by interferons in human prostate stromal and epithelial cells

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