HEPATITIS-B VIRUS HBX PROTEIN ACTIVATES RAS-GTP COMPLEX-FORMATION AND ESTABLISHES A RAS, RAF, MAP KINASE SIGNALING CASCADE
HEPATITIS-B VIRUS HBX PROTEIN ACTIVATES RAS-GTP COMPLEX-FORMATION AND ESTABLISHES A RAS, RAF, MAP KINASE SIGNALING CASCADE
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DOI：
10.1073/pnas.91.22.10350
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发表时间：
1994-10-25
影响因子：
11.1
通讯作者：
SCHNEIDER, RJ
中科院分区：
文献类型：
--
作者：
BENN, J;SCHNEIDER, RJ
乙型肝炎病毒产生一种小型（154 个氨基酸）转录反式激活蛋白 HBx，它是病毒感染所需的，并且与病毒介导的肝脏肿瘤发生有关。然而，HBx 活性的分子机制及其对细胞增殖的可能影响仍不清楚。许多研究表明，HBx 可能通过间接激活转录因子（可能是通过影响细胞信号传导途径）来刺激转录。我们现在提出的生化证据表明，HBx 激活 Ras 并快速诱导连接 Ras、Raf 和丝裂原激活蛋白激酶（MAP 激酶）的细胞质信号级联，从而导致转录反式激活。 HBx 强烈提高 GTP 结合 Ras、激活和磷酸化 Raf 以及酪氨酸磷酸化和激活 MAP 激酶的水平。 HBx 对转录因子 AP-1 的反式激活可通过抑制 Ras 或 Raf 活性来阻断，但不能通过抑制 Ca2+- 和二酰甘油依赖性蛋白激酶 C 来阻断。HBx 还被发现可以刺激血清饥饿细胞中的 DNA 合成。因此，乙型肝炎病毒 HBx 蛋白会刺激 Ras-GTP 复合物的形成，并通过 Raf 和 MAP 激酶促进下游信号传导，并可能影响细胞增殖。
Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have remained obscure. A number of studies suggest that HBx may stimulate transcription by indirectly activating transcription factors, possibly by influencing cell signaling pathways. We now present biochemical evidence that HBx activates Ras and rapidly induces a cytoplasmic signaling cascade linking Ras, Raf, and mitogen-activated protein kinase (MAP kinase), leading to transcriptional transactivation. HBx strongly elevates levels of GTP-bound Ras, activated and phosphorylated Raf, and tyrosine-phosphorylated and activated MAP kinase. Transactivation of transcription factor AP-1 by HBx is blocked by inhibition of Ras or Raf activities but not by inhibition of Ca2+- and diacylglycerol-dependent protein kinase C. HBx was also found to stimulate DNA synthesis in serum-starved cells. The hepatitis B virus HBx protein therefore stimulates Ras-GTP complex formation and promotes downstream signaling through Raf and MAP kinases, and may influence cell proliferation.