title: PTEN C-terminal deletion causes genomic instability and tumor development.
abstract: Tumor suppressor PTEN controls genomic stability and inhibits tumorigenesis. The N-terminal phosphatase domain of PTEN antagonizes the PI3K/AKT pathway, but its C-terminal function is less defined. Here, we describe a knockin mouse model of a nonsense mutation that results in the deletion of the entire Pten C-terminal region, referred to as Pten(ΔC). Mice heterozygous for Pten(ΔC) develop multiple spontaneous tumors, including cancers and B cell lymphoma. Heterozygous deletion of the Pten C-terminal domain also causes genomic instability and common fragile site rearrangement. We found that Pten C-terminal disruption induces p53 and its downstream targets. Simultaneous depletion of p53 promotes metastasis without influencing the initiation of tumors, suggesting that p53 mainly suppresses tumor progression. Our data highlight the essential role of the PTEN C terminus in the maintenance of genomic stability and suppression of tumorigenesis.
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PRC; Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Jinxue
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Lamb
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PRC; Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Kang
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Gu
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address: wes2007@med.cornell.edu.
authors.forename: Wen Hong
authors.initials: WH
authors.lastname: Shen
authors.affiliation: Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PRC; Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address: yinyuxin@hsc.pku.edu.cn.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D042822:Genomic Instability; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D017354:Point Mutation; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse