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HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage

Title
HER2 stabilizes survivin while concomitantly down-regulating survivin gene transcription by suppressing Notch cleavage
Author
신인철
Keywords
Akt; breast cancer; extracellular-signal-regulated kinase (ERK); human epidermal growth factor receptor 2 (HER2); Notch1; survivin
Issue Date
2013-04
Publisher
PORTLAND PRESS LTD,
Citation
BIOCHEMICAL JOURNAL, April 2013, 451, P.123-134
Abstract
In breast cancer, the HER2 (human epidermal growth factor receptor 2) receptor tyrosine kinase is associated with extremely poor prognosis and survival. Notch signalling has a key role in cell-fate decisions, especially in cancer-initiating cells. The Notch intracellular domain produced by Notch cleavage is translocated to the nucleus where it activates transcription of target genes. To determine the combinatory effect of HER2 and Notch signalling in breast cancer, we investigated the effect of HER2 on Notch-induced cellular phenomena. We found the down-regulation of Notch-dependent transcriptional activity by HER2 overexpression. Also, the HER2/ERK (extracellular-signal-regulated kinase) signal pathway down-regulated the activity of gamma-secretase. When we examined the protein level of Notch target genes in HER2-overexpressing cells, we observed that the level of survivin, downstream of Notch, increased in HER2 cells. We found that activation of ERK resulted in a decrease in XAF1 [XIAP (X-linked inhibitor of apoptosis)-associated factor 1] which reduced the formation of the XIAP-XAF1 E3 ligase complex to ubiquitinate survivin. In addition, Thr(34) of survivin was shown to be the most important residue in determining survivin stability upon phosphorylation after HER2/Akt/CDK1 (cyclin-dependent kinase 1)-cyclin B1 signalling The results of the present study show the combinatorial effects of HER2 and Notch during breast oncogenesis.
URI
http://www.biochemj.org/content/451/1/123http://hdl.handle.net/20.500.11754/44320
ISSN
1470-8728
DOI
10.1042/BJ20121716
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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