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  • Title: The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression.
    Author: Samraj AK, Stroh C, Fischer U, Schulze-Osthoff K.
    Journal: Oncogene; 2006 Jan 12; 25(2):186-97. PubMed ID: 16116473.
    Abstract:
    Tyrosine kinases of the Src family have been implicated in key biological processes. Here, we provide evidence that p56(Lck), a lymphoid-specific Src kinase, is involved in the activation of the mitochondrial apoptosis pathway. Lck-deficient T cells were completely resistant to anticancer drugs. In contrast, apoptosis sensitivity to death receptors was not altered, indicating a specific interference of Lck with the mitochondrial pathway. Re-expression of Lck restored sensitivity to drug-induced apoptosis and triggered mitochondrial cytochrome c release and caspase activation. Further analysis identified that the sensitization by Lck was independent of classical mediators of T-cell signaling, but essentially involved the Bcl-2 protein Bak. Expression of Bak was completely absent in Lck-deficient cells, while re-expression of Lck transcriptionally triggered Bak expression and conferred sensitivity to apoptosis, associated with a proapoptotic conformational change of Bak. Furthermore, in vitro the truncated fragment of Bid specifically activated Bak and cytochrome c release only from mitochondria of Lck-expressing cells. These results do not only demonstrate a sentinel role of Lck in drug resistance but also delineate a hitherto unknown pathway of Src kinases in regulation of Bcl-2 proteins.
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