title: Δ40p53α suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells.
abstract: Splice variants of certain genes impact on genetic biodiversity in mammals. The tumor suppressor TP53 gene (encoding p53) plays an important role in the regulation of tumorigenesis in hepatocellular carcinoma (HCC). Δ40p53α is a naturally occurring p53 isoform that lacks the N-terminal transactivation domain, yet little is known about the role of Δ40p53α in the development of HCC. Here, we first report on the role of Δ40p53α in HCC cell lines. In the TP53+/Δ40cell clones, clonogenic activity and cell survival dramatically decreased, whereas the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive cells and p21 (also known as WAF1, CIP1 and CDKN1A) expression significantly increased. These observations were clearly attenuated in the TP53+/Δ40cell clones after Δ40p53α knockdown. In addition, exogenous Δ40p53 expression significantly suppressed cell growth in HCC cells with wild-type TP53, and in those that were mutant or null for TP53 Notably, Δ40p53α-induced tumor suppressor activity was markedly attenuated in cells expressing the hot-spot mutant Δ40p53α-R175H, which lacks the transcription factor activity of p53. Moreover, Δ40p53α expression was associated with increased full-length p53 protein expression. These findings enhance the understanding of the molecular pathogenesis of HCC and show that Δ40p53α acts as an important tumor suppressor in HCC cells.
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ota
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan hnakao@aichi-med-u.ac.jp.
authors.forename: Haruhisa
authors.identifier: 0000-0003-1794-0886
authors.initials: H
authors.lastname: Nakao
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Sivasundaram
authors.initials: S
authors.lastname: Karnan
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Md
authors.initials: M
authors.lastname: Wahiduzzaman
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohashi
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yukiomi
authors.initials: Y
authors.lastname: Nakade
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sato
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
authors.affiliation: Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoneda
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D016922:Cellular Senescence; D002999:Clone Cells; D059585:G1 Phase Cell Cycle Checkpoints; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010641:Phenotype; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53
keywords: Gene expression; Gene targeting; Liver cancer; Tumorigenesis; Δ40p53