Abstract
The Rac1/JNK cascade plays important roles in DNA damage-induced apoptosis. However, how this cascade is activated upon DNA damage remains to be fully understood. We show here that, in untreated cells, Tiam1, a Rac1-specific guanine nucleotide exchange factor, is phosphorylated by casein kinase 1 (CK1) at its C terminus, leading to Skp, Cullin, F-box-containing(β-TrCP) recognition, ubiquitination, and proteasome-mediated degradation. Upon DNA-damaging anticancer drug treatment, CK1/β-TrCP-mediated Tiam1 degradation is abolished, and the accumulated Tiam1 contributes to downstream activation of Rac1/JNK. Consistently, tumor cells overexpressing Tiam1 are hypersensitive to DNA-damaging drug treatment. In xenograft mice, Tiam1-high cells are more susceptible to doxorubicin treatment. Thus, our results uncover that inhibition of proteasome-mediated Tiam1 degradation is an upstream event leading to Rac1/JNK activation and cell apoptosis in response to DNA-damaging drug treatment.
Highlights
DNA damage-induced activation of the Rac1/JNK cascade is required for apoptosis
Initially aimed to search upstream guanine nucleotide exchange factor (GEF) for Rac1 activation, we found incidentally that -TrCPdependent T cell lymphoma invasion and metastasis 1 (Tiam1) polyubiquitination/degradation is inhibited in response to CPT- or DOX-induced DNA damage signaling and that subsequent Tiam1 accumulation contributes to Rac1/ JNK activation and apoptosis
Tiam1, a specific GEF for Rac1 activation, is important for Rac1 signaling during tumorigenesis [17]
Summary
Results: Upon chemotherapeutic drug treatment, Tiam, a Rac1-specific GEF, is accumulated through inhibition of CK1/ -TrCP-mediated degradation. Upon DNA-damaging anticancer drug treatment, CK1/ -TrCP-mediated Tiam degradation is abolished, and the accumulated Tiam contributes to downstream activation of Rac1/JNK. Our results uncover that inhibition of proteasome-mediated Tiam degradation is an upstream event leading to Rac1/JNK activation and cell apoptosis in response to DNA-damaging drug treatment. Plitidepsin, a potent inducer of apoptosis, was dependent on the Rac1/JNK pathway to function [11] All of these results strongly suggest that the Rac1/JNK cascade is important in DNA damage response-induced cell apoptosis. Initially aimed to search upstream GEFs for Rac activation, we found incidentally that -TrCPdependent Tiam polyubiquitination/degradation is inhibited in response to CPT- or DOX-induced DNA damage signaling and that subsequent Tiam accumulation contributes to Rac1/ JNK activation and apoptosis
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