The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells
dc.contributor.author | Wollmann, Wyatt | |
dc.contributor.author | Goodman, Mike L. | |
dc.contributor.author | Bhat-Nakshatri, Poornima | |
dc.contributor.author | Kishimoto, Hiromitsu | |
dc.contributor.author | Goulet, Robert J. | |
dc.contributor.author | Mehrotra, Sanjana | |
dc.contributor.author | Morimiya, Akira | |
dc.contributor.author | Badve, Sunil | |
dc.contributor.author | Nakshatri, Harikrishna | |
dc.date.accessioned | 2019-04-09T20:35:21Z | |
dc.date.available | 2019-04-09T20:35:21Z | |
dc.date.issued | 2005-05-01 | |
dc.description.abstract | Macrophage inhibitory cytokine 1 (MIC-1), a divergent member of the transforming growth factor beta superfamily, plays a role in the progression of a number of cancers, including breast, gastric, prostate and colorectal carcinomas. Serum MIC-1 levels are elevated in patients with metastatic prostate, breast and colorectal carcinomas. In vitro studies have revealed a cell type-specific role for MIC-1 in senescence and apoptosis. MIC-1 activates the survival kinase AKT/PKB in neuronal cells. Depending on the cell type, it activates or represses the MAP kinases ERK1/2. Mechanisms responsible for an increased MIC-1 expression in cancers and the consequences of MIC-1 overexpression, however, are not known. In this study, we show that AKT/PKB directly regulates the expression of MIC-1 in breast cancer cells. Sequences within −88 to +30 of the MIC-1 promoter are required for the AKT-mediated induction of MIC-1. This region of the promoter contains two SP-1 binding sites (SP-1B and SP-1C), which bind to the SP-1 and SP-3 proteins. Mutation of SP-1C but not SP-1B reduced the AKT-mediated activation of MIC-1. MIC-1 increased the basal ERK1 phosphorylation and prolonged the estrogen-stimulated ERK1 phosphorylation in MCF-7 breast cancer cells without altering the phosphorylation status of AKT/PKB. Immunohistochemistry with MIC-1 antibody revealed an MIC-1 expression within the cancer cells of primary breast cancer and in the MCF-7 xenografts. Furthermore, a limited analysis of RNA from primary breast cancers revealed an overexpression of MIC-1 in tumors, compared with normal tissues. These results suggest that AKT/PKB through MIC-1 could regulate the ERK1 activity and the MIC-1 expression levels may serve as a surrogate marker for the AKT activation in tumors. | en_US |
dc.identifier.citation | Wollmann, W., Goodman, M. L., Bhat-Nakshatri, P., Kishimoto, H., Goulet, R. J., Mehrotra, S., … Nakshatri, H. (2005). The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells. Carcinogenesis, 26(5), 900–907. https://doi.org/10.1093/carcin/bgi031 | en_US |
dc.identifier.doi | 10.1093/carcin/bgi031 | |
dc.identifier.issn | 0143-3334 | |
dc.identifier.uri | https://hdl.handle.net/1805/18811 | |
dc.language.iso | en_US | en_US |
dc.publisher | Oxford University Press | en_US |
dc.subject | CA-AKT | en_US |
dc.subject | constitutively active AKT | en_US |
dc.subject | EMSA | en_US |
dc.subject | electrophoretic mobility shift assay | en_US |
dc.subject | ERα | en_US |
dc.subject | estrogen receptor alpha | en_US |
dc.subject | KD-AKT | en_US |
dc.subject | kinase dead AKT | en_US |
dc.subject | MIC-1 | en_US |
dc.subject | macrophage inhibitory cytokine 1 | en_US |
dc.subject | RT–PCR | en_US |
dc.subject | reverse transcription–polymerase chain reaction | en_US |
dc.title | The macrophage inhibitory cytokine integrates AKT/PKB and MAP kinase signaling pathways in breast cancer cells | en_US |
dc.type | Article | en_US |