title: HPV-16 impairs the subcellular distribution and levels of expression of protein phosphatase 1γ in cervical malignancy.
abstract: BACKGROUND
  The high risk Human Papillomavirus (HPV) E6 oncoproteins play an essential role in the development of cervical malignancy. Important cellular targets of E6 include p53 and the PDZ domain containing substrates such as hScrib and Dlg. We recently showed that hScrib activity was mediated in part through recruitment of protein phosphatase 1γ (PP1γ).
  
  
  METHODS
  Expression patterns of hScrib and PP1γ were assessed by immunohistochemistry of HPV-16 positive cervical intraepithelial neoplasm (CIN), classified as CIN1 (n = 4), CIN2 (n = 8), CIN3 (n = 8), cervical carcinoma tissues (n = 11), and HPV-negative cervical tissues (n = 8), as well as by subfractionation assay of the HPV-16 positive cervical cancer cell lines, CaSki and SiHa. To explore the effects of the HPV-16 oncoproteins, we have performed siRNA knockdown of E6/E7 expression, and monitored the effects on the expression patterns of hScrib and PP1γ.
  
  
  RESULTS
  We show that PP1γ levels in HPV-16 positive tumour cells are reduced in an E6/E7 dependent manner. Residual PP1γ in these cells is found mostly in the cytoplasm as opposed to the nucleus where it is predominantly found in normal cells. We have found a striking concordance with redistribution in the pattern of expression (9/11; 81.8%) and loss of PP1γ expression in HPV-16 positive cervical tumours (2/11; 18.2%). Furthermore, this loss of PP1γ expression and redistribution in the pattern of expression occurs progressively as the lesions develop (8/8; 100%).
  
  
  CONCLUSIONS
  Together, these results suggest that PP1γ may be a novel target of the HPV-16 oncoproteins and indicate that it might be a potential novel biomarker for HPV-16 induced malignancy.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. thinmu@yahoo.co.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Seiki
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. nagasakak-tky@umin.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagasaka
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano-99, I-34012, Trieste, Italy. Christian.Kranjec@icgeb.org.
authors.forename: Christian
authors.initials: C
authors.lastname: Kranjec
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. kkawana-tky@umin.org.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. daichimaeda@gmail.com.
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. kamotomoka@yahoo.co.jp.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. ayumikidu246@yahoo.co.jp.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. yokomatsumoto@mac.com.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. tarimoto-tky@umin.ac.jp.
authors.forename: Takahide
authors.initials: T
authors.lastname: Arimoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. osamuwh-tky@umin.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. katsutoshi-tky@umin.ac.jp.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, Teikyo University, Tokyo, 173-8605, Japan. nakagawas-tky@umin.ac.jp.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan. tetu-tky@umin.ac.jp.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. mfukayama-tky@umin.org.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano-99, I-34012, Trieste, Italy. banks@icgeb.org.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. yutakaos-tky@umin.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. fujiit-tky@umin.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
mesh_terms: D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D052162:Human papillomavirus 16; D006801:Humans; D007150:Immunohistochemistry; D042541:Intracellular Space / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; D054645:Protein Phosphatase 1