title: Mechanism of angiopoietin-1 upregulation in Kaposi's sarcoma-associated herpesvirus-infected PEL cell lines.
abstract: Angiopoietin-1 (ANGPT-1) is a secreted glycoprotein that was first characterized as a ligand of the Tie2 receptor. In a previous study using microarray analysis, we found that the expression of ANGPT-1 was upregulated in Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cell lines compared with that in uninfected Burkitt and other leukemia cell lines. Other authors have also reported focal expression of ANGPT-1 mRNA in biopsy specimens of Kaposi's sarcoma (KS) tissue from patients with AIDS. Here, to confirm these findings, we examined the expression and secretion levels of ANGPT-1 in KSHV-infected PEL cell lines and address the mechanisms of ANGPT-1 transcriptional regulation. We also showed that ANGPT-1 was expressed and localized in the cytoplasm and secreted into the supernatant of KSHV-infected PEL cells. Deletion studies of the regulatory region revealed that the region encompassing nucleotides -143 to -125 of the ANGPT-1-regulating sequence was responsible for this upregulation. Moreover, an electrophoretic mobility shift assay and chromatin immunoprecipitation, followed by quantitative PCR, suggested that some KSHV-infected PEL cell line-specific DNA-binding factors, such as OCT-1, should be involved in the upregulation of ANGPT-1 in a sequence-dependent manner.
  
  
  OBJECTIVE
  We confirmed that ANGPT-1 was expressed in and secreted from KSHV-infected PEL cells and that the transcriptional activity of ANGPT-1 was upregulated. A 19-bp fragment was identified as the region responsible for ANGPT-1 upregulation through binding with OCT-1 as a core factor in PEL cells. This study suggests that ANGPT-1 is overproduced in KSHV-infected PEL cells, which could affect the pathophysiology of AIDS patients with PEL.
authors: Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Xin
authors: X
authors: Zheng
authors: Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Eriko
authors: E
authors: Ohsaki
authors: Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan kueda@virus.med.osaka-u.ac.jp.
authors: Keiji
authors: K
authors: Ueda
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D000951:Antigens, Neoplasm; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004252:DNA Mutational Analysis; D024202:Electrophoretic Mobility Shift Assay; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion; D015854:Up-Regulation
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D000951:Antigens, Neoplasm; D050811:Octamer Transcription Factor-1; C412325:SAGE1 protein, human
references: Cell. 1996 Dec 27;87(7):1161-9
references: 8980223
references: Blood. 1996 Jul 1;88(1):242-51
references: 8704180
references: J Virol. 1998 Jun;72(6):4980-8
references: 9573267
references: J Virol. 1999 Feb;73(2):1438-46
references: 9882349
references: J Virol. 1999 Aug;73(8):6646-60
references: 10400762
references: Virus Res. 2006 Dec;122(1-2):85-94
references: 16920214
references: J Virol. 2007 Apr;81(8):3980-91
references: 17287278
references: Cancer Res. 2007 May 1;67(9):4042-51
references: 17483315
references: Cancer Res. 2008 Jun 15;68(12):4640-8
references: 18559509
references: Virus Res. 2009 Jan;139(1):74-84
references: 19027806
references: Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77
references: 19234476
references: Biochem Biophys Res Commun. 2010 Apr 9;394(3):482-7
references: 20175997
references: J Microbiol. 2010 Apr;48(2):206-12
references: 20437153
references: Nat Rev Cancer. 2010 Aug;10(8):575-85
references: 20651738
references: Cancer Res. 2011 Sep 1;71(17):5717-27
references: 21778249
references: Blood. 2011 Nov 10;118(19):5344-54
references: 21881052
references: J Med Virol. 2012 May;84(5):786-91
references: 22431027
references: PLoS Pathog. 2012 Sep;8(9):e1002927
references: 23028325
references: J Virol. 2012 Nov;86(22):12176-86
references: 22933289
references: Trends Mol Med. 2013 Jan;19(1):31-9
references: 23182855
references: Cell Host Microbe. 2013 Apr 17;13(4):429-40
references: 23601105
references: J Virol. 2013 Jun;87(11):6326-35
references: 23536671
references: J Immunol. 2013 Aug 1;191(3):1476-85
references: 23804715
references: J Virol. 2013 Oct;87(19):10816-27
references: 23903842
references: PLoS Pathog. 2014 Jan;10(1):e1003858
references: 24391506
references: Mol Cell Biol. 2014 Feb;34(3):386-99
references: 24248600
references: Am J Pathol. 2000 Jun;156(6):2179-83
references: 10854238
references: Semin Cancer Biol. 2000 Oct;10(5):367-81
references: 11100885
references: J Virol. 2001 Feb;75(4):1864-9
references: 11160685
references: J Virol. 2002 Jun;76(12):6185-96
references: 12021352
references: J Virol. 2002 Dec;76(23):12044-54
references: 12414946
references: J Virol. 2003 Feb;77(4):2779-83
references: 12552022
references: J Virol. 2003 Jun;77(11):6188-96
references: 12743275
references: Virology. 2003 Nov 10;316(1):64-74
references: 14599791
references: J Biol Chem. 2004 Mar 26;279(13):12794-803
references: 14715662
references: Virology. 2004 Aug 1;325(2):225-40
references: 15246263
references: J Virol. 2004 Sep;78(18):9936-46
references: 15331727
references: Cell. 1990 Feb 9;60(3):375-86
references: 2302733
references: J Virol. 1990 Jun;64(6):3025-32
references: 2159560
references: Science. 1994 Dec 16;266(5192):1865-9
references: 7997879
references: N Engl J Med. 1995 May 4;332(18):1186-91
references: 7700311
references: Blood. 1995 Aug 15;86(4):1276-80
references: 7632932
references: Nature. 1998 Jan 1;391(6662):86-9
references: 9422510