title: The protein interacting with carboxyl terminus-1 codon 389 polymorphism impairs protein interacting with carboxyl terminus-1 function and is a risk factor for uterine cervical cancer.
abstract: PICT-1 is a nucleolar protein with various tumor suppressor functions. Recently, PICT-1 expression was reported to be dramatically reduced in several cancers. To investigate the role of PICT-1 in uterine cervical carcinogenesis, we examined its gene mutations, protein expression, cellular localization, and effect on p53 stabilization. PCR-SSCP analysis of the entire coding region of PICT-1 showed that a polymorphism at codon 389 may increase the risk of uterine cervical cancers, and also identified a novel missense mutation. Expression of wild-type PICT-1 inhibited the degradation of p53 in the presence or absence of HPV 18 E6 viral protein in vitro, while the expression of codon 389 polymorphic PICT-1 had a diminished inhibitory effect on p53 degradation. Moreover, we observed that PICT-1 degradation was induced both independently and cooperatively by E6 and E7 proteins from high-risk HPVs, but only marginal degradation was observed with proteins from low-risk HPV. Immunohistochemical staining of tumor samples revealed that lower levels of PICT-1 were observed in samples from CIN III and cervical cancer tissues, compared to normal cervical epithelium and CIN I, II tissues (P < 0.05). The reduction of PICT-1 may therefore be an early event in uterine cervical tumorigenesis. Our results indicated that PICT-1 counteracts HPV-induced p53 degradation and that aberrant PICT-1 function may contribute towards inactivating p53. Therefore, PICT-1 may play a critical role during the pathogenesis of uterine cervical cancers.
authors.affiliation: Faculty of Life Sciences, Department of Oncology, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yoshimoto
authors.affiliation: Faculty of Life Sciences, Department of Oncology, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Tokuda
authors.affiliation: Department of Obstetrics & Gynecology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Nishiwaki
authors.affiliation: Department of Obstetrics & Gynecology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sengoku
authors.affiliation: Faculty of Life Sciences, Department of Oncology, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yaginuma
mesh_terms: D045744:Cell Line, Tumor; D003062:Codon; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells / Q000821:virology; D052161:Human papillomavirus 18 / Q000472:pathogenicity; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D011110:Polymorphism, Genetic; D055550:Protein Stability; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C500712:NOP53 protein, human; D009856:Oncogene Proteins, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: PICT-1; carcinogenesis; polymorphism; risk factor; uterine cervical cancer