TGF-Β對於肝癌細胞死亡的調控與機制之研究(4/5)
Date Issued
2003-05-26
Date
2003-05-26
Author(s)
Chen, Ruey-Hwa
DOI
912321B002001
Abstract
Death associated protein kinase (DAP-kinase) is a
calcium/calmodulin-dependent serine/threonine kinase, and participates in various
apoptosis systems. However, its apoptosis-promoting mechanism is poorly
understood. Here, we demonstrate that DAP-kinase suppresses integrin-mediated
cell adhesion and signal transduction, whereas dominant-negative interference of this
kinase promotes adhesion. This effect of DAP-kinase is neither a consequence of
apoptosis, nor a result of decreased expression of integrins. Rather, DAP-kinase
downregulates integrin activity through an inside-out mechanism. We present
evidence indicating that this adhesion-inhibitory effect accounts for a major
mechanism of the apoptosis induced by DAP-kinase. First, in growth-arrested
fibroblasts, DAP-kinase triggers apoptosis in cells plated on fibronectin, but does not
affect the death of cells on poly-L-lysine. Second, in epithelial cells, DAP-kinase
induces apoptosis in the anoikis-sensitive MCF10A cells, but not in the
anoikis-resistant BT474 cells. Most importantly, the apoptosis-promoting effect of
DAP-kinase is completely abolished by enforced activation of integrin-mediated
signaling pathways from either integrin itself or its downstream effector FAK.
Finally, we show integrin or FAK activation blocks the ability of DAP-kinase to
upregulate p53. Our results indicate that DAP-kinase exerts apoptotic effect by
suppressing integrin functions and integrin-mediated survival signals, thereby
activating a p53-dependent apoptotic pathway.
Publisher
臺北市：國立臺灣大學醫學院分子醫學研究所
Type
journal article
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