title: WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation.
abstract: Oncogene-induced senescence (OIS) or apoptosis through the DNA-damage response is an important barrier of tumorigenesis. Overcoming this barrier leads to abnormal cell proliferation, genomic instability, and cellular transformation, and finally allows cancers to develop. However, it remains unclear how the OIS barrier is overcome. Here, we show that the E3 ubiquitin ligase WD repeat and SOCS box-containing protein 1 (WSB1) plays a role in overcoming OIS. WSB1 expression in primary cells helps the bypass of OIS, leading to abnormal proliferation and cellular transformation. Mechanistically, WSB1 promotes ATM ubiquitination, resulting in ATM degradation and the escape from OIS. Furthermore, we identify CDKs as the upstream kinase of WSB1. CDK-mediated phosphorylation activates WSB1 by promoting its monomerization. In human cancer tissue and in vitro models, WSB1-induced ATM degradation is an early event during tumorigenic progression. We suggest that WSB1 is one of the key players of early oncogenic events through ATM degradation and destruction of the tumorigenesis barrier. Our work establishes an important mechanism of cancer development and progression in premalignant lesions.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Seung Baek
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Department of Medical Education, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon 404834, Republic of Korea.
authors.forename: Sang-Yeop
authors.initials: SY
authors.lastname: Yi
authors.affiliation: Department of Surgery, School of Medicine, Kyung Hee University, Seoul 130872, Republic of Korea.
authors.forename: Sang-Ah
authors.initials: SA
authors.lastname: Han
authors.affiliation: Department of Family Medicine, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon 404834, Republic of Korea.
authors.forename: Sun-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University, Seoul 130872, Republic of Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Kyung Hee University, Seoul 130872, Republic of Korea.
authors.forename: Seo-Yun
authors.initials: SY
authors.lastname: Tong
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D009857:Oncogenes; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C120287:WSB1 protein, human; C503398:Wsb1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins