Kaposi's sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1α to upregulate RTA expression during hypoxia:: Latency control under low oxygen conditions

被引:110
作者
Cai, Qiliang
Lan, Ke
Verma, Subhash C.
Si, Huaxin
Lin, Doug
Robertson, Erle S.
机构
[1] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA USA
[2] Univ Penn, Sch Med, Tumor Virol Program, Philadelphia, PA USA
关键词
D O I
10.1128/JVI.00689-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Hypoxia can induce lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) in primary effusion lymphoma (PEL) cells. However, the molecular mechanism of lytic reactivation of KSHV by hypoxia remains unclear. Here we show that the latency-associated nuclear antigen (LANA), which plays a crucial role in modulating viral and cellular gene expression, directly associated with a low oxygen responder, hypoxia-inducible factor-1 alpha (HIF-1 alpha). LANA enhanced not only the transcriptional activities of HIF-1 alpha but also its mRNA level. Coimmunoprecipitation and immunotluorescence studies documented a physical interaction between LANA and HIF-1 alpha in transiently transfected 293T cells as well as in PEL cell lines during hypoxia. Through sequence analysis, several putative hypoxia response elements (HRE-1 to -6) were identified in the essential lytic gene Rta promoter. Reporter assays showed that HRE-2 (-1130 to -1123) and HRE-5 and HRE-6 (+234 to +241 and +812 to +820, respectively, within the intron sequence) were necessary and sufficient for the LANA-mediated HIF-1 alpha response. Electrophoretic mobility shift assays showed HIF-1 alpha dependent binding of a LANA protein complex specifically to the HRE-2, -5, and -6 motifs within the promoter regulatory sequences. This study demonstrates that hypoxia-induced KSHV lytic replication is mediated at least in part through cooperation of HIF-1 alpha with LANA bound to the HRE motifs of the Rta promoter.
引用
收藏
页码:7965 / 7975
页数:11
相关论文
共 40 条
  • [1] Transcriptional coactivation of c-Jun by the KSHV-encoded LANA
    An, JB
    Sun, YP
    Rettig, MB
    [J]. BLOOD, 2004, 103 (01) : 222 - 228
  • [2] Aster JC, 1997, J BIOL CHEM, V272, P11336
  • [3] Oxygen sensing and molecular adaptation to hypoxia
    Bunn, HF
    Poyton, RO
    [J]. PHYSIOLOGICAL REVIEWS, 1996, 76 (03) : 839 - 885
  • [4] Targeting gene expression to hypoxic tumor cells
    Dachs, GU
    Patterson, AV
    Firth, JD
    Ratcliffe, PJ
    Townsend, KMS
    Stratford, IJ
    Harris, AL
    [J]. NATURE MEDICINE, 1997, 3 (05) : 515 - 520
  • [5] Dagnon K, 2005, CLIN CANCER RES, V11, P993
  • [6] Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus
    Davis, DA
    Rinderknecht, AS
    Zoeteweij, JP
    Aoki, Y
    Read-Connole, EL
    Tosato, G
    Blauvelt, A
    Yarchoan, R
    [J]. BLOOD, 2001, 97 (10) : 3244 - 3250
  • [7] Auto-activation of the rta gene of human herpesvirus-8 Kaposi's sarcoma-associated herpesvirus
    Deng, HY
    Young, A
    Sun, R
    [J]. JOURNAL OF GENERAL VIROLOGY, 2000, 81 : 3043 - 3048
  • [8] Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma
    Dupin, N
    Fisher, C
    Kellam, P
    Ariad, S
    Tulliez, M
    Franck, N
    van Marck, E
    Salmon, D
    Gorin, I
    Escande, JP
    Weiss, RA
    Alitalo, K
    Boshoff, C
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (08) : 4546 - 4551
  • [9] Fink T, 2002, BLOOD, V99, P2077, DOI 10.1182/blood.V99.6.2077
  • [10] Forsythe JA, 1996, MOL CELL BIOL, V16, P4604