title: DNA damage induces the accumulation of Tiam1 by blocking β-TrCP-dependent degradation.
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.
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China, the Tsinghua-Peking Center for Life Sciences, Beijing 100084, China, and.
authors.forename: Guixin
authors.initials: G
authors.lastname: Zhu
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Fan
authors.affiliation: the School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Ding
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Mu
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liang
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Ding
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Binlu
authors.initials: B
authors.lastname: Huang
authors.affiliation: From the Key Laboratory of Protein Science of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China, wwu@mail.tsinghua.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D047389:Casein Kinase I / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C471644:BTRC protein, human; D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D004317:Doxorubicin; D044767:Ubiquitin-Protein Ligases; D047389:Casein Kinase I; D048031:JNK Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein
keywords: Apoptosis; Chemotherapy; DNA Damage; E3 Ubiquitin Ligase; Rac1; Tiam1; c-Jun N-terminal Kinase (JNK)
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