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.
Keywords:
Apoptosis; Chemotherapy; DNA Damage; E3 Ubiquitin Ligase; Rac1; Tiam1; c-Jun N-terminal Kinase (JNK).
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / toxicity
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Apoptosis / genetics
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Apoptosis / physiology*
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Casein Kinase I / metabolism
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DNA Damage / drug effects
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DNA Damage / physiology*
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Doxorubicin / toxicity
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Female
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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HEK293 Cells
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HeLa Cells
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Mice, Nude
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Signal Transduction / genetics
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Signal Transduction / physiology*
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / physiology
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Uterine Cervical Neoplasms* / drug therapy
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Uterine Cervical Neoplasms* / genetics
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Uterine Cervical Neoplasms* / metabolism
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Xenograft Model Antitumor Assays
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beta-Transducin Repeat-Containing Proteins / genetics
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beta-Transducin Repeat-Containing Proteins / metabolism*
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rac1 GTP-Binding Protein / metabolism
Substances
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Antibiotics, Antineoplastic
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BTRC protein, human
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Guanine Nucleotide Exchange Factors
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RAC1 protein, human
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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TIAM1 protein, human
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beta-Transducin Repeat-Containing Proteins
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Doxorubicin
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Ubiquitin-Protein Ligases
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Casein Kinase I
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JNK Mitogen-Activated Protein Kinases
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rac1 GTP-Binding Protein