The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc
The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc
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DOI：
10.1128/jvi.00804-07
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发表时间：
2007-10-01
影响因子：
5.4
通讯作者：
Hayward, Diane
中科院分区：
文献类型：
--
作者：
Liu, Jianyong;Martin, Heather J.;Hayward, Diane
卡波西肉瘤相关疱疹病毒(KSHV)潜伏期相关核抗原(LANA)蛋白具有多效性。LANA参与了KSHV相关的致病过程，部分是通过LANA与丝氨酸-苏氨酸激酶糖原合成酶-3(GSK-3)的相互作用和P-连环蛋白的稳定而促进细胞进入S时相。我们现在表明，LANA影响另一种参与细胞周期调节的蛋白质c-Myc的活性。对c-Myc编码序列的测序表明，在KSHV阳性的原发渗出性淋巴瘤(PEL)细胞系中，c-Myc在调控c-Myc蛋白稳定性的N端区域为野生型。尽管如此，PEL细胞中的c-Myc是稳定的。在表达LANA的细胞中，核GSK-3的失活减少了Thr58处c-Myc的磷酸化，并通过减少c-Myc泛素化而有助于c-Myc的稳定。Ser62上c-Myc的磷酸化也影响c-Myc的稳定性和功能。我们现在发现，LANA增加了磷酸化的细胞外信号调节激酶1(ERK1)的水平，并增加了Ser62上c-Myc的ERK磷酸化。LANA还与c-Myc相互作用，这种相互作用需要147~220个c-Myc氨基酸。LANA(L1006P)保留了与c-Myc结合并激活ERK1的能力，表明这些事件不需要LANA与GSK-3相互作用。因此，LANA稳定c-Myc；阻止Thr58处c-Myc的磷酸化，这是促进Myc诱导的细胞凋亡的事件；并独立地刺激Ser62处的c-Myc的磷酸化，这一事件转录上激活了c-Myc。LANA介导的对c-Myc功能的调控可能通过诱导c-Myc调节的细胞基因以及刺激细胞周期进程来促进KSHV相关肿瘤的发生。
The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) protein is functionally pleiotropic. LANA contributes to KSHV-associated pathogenesis, in part, by increasing entry of cells into S phase through a process that is driven by LANA interaction with the serine-threonine kinase glycogen synthase kinase 3 (GSK-3) and stabilization of P-catenin. We now show that LANA affects the activity of another protein involved in cell cycle regulation, c-Myc. Sequencing of c-Myc coding sequences revealed that c-Myc in KSHV-positive primary effusion lymphoma (PEL) cell lines is wild type in the N-terminal region that regulates c-Myc protein stability. Despite this, c-Myc in PEL cells is stabilized. In LANA-expressing cells, inactivation of nuclear GSK-3 reduced phosphorylation of c-Myc at Thr58 and contributed to c-Myc stabilization by decreasing c-Myc ubiquitination. Phosphorylation of c-Myc on Ser62 also affects c-Myc stability and function. We now show that LANA increases the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) and increases ERK phosphorylation of c-Myc on Ser62. LANA also interacted with c-Myc, and c-Myc amino acids 147 to 220 were required for this interaction. LANA (L1006P) retained the ability to bind to c-Myc and activate ERK1, indicating that these events did not require LANA interaction with GSK-3. Thus, LANA stabilizes c-Myc; prevents the phosphorylation of c-Myc at Thr58, an event that promotes Myc-induced apoptosis; and independently stimulates phosphorylation of c-Myc at Ser62, an event that transcriptionally activates c-Myc. LANA-mediated manipulation of c-Myc function is likely to contribute to KSHV-associated tumorigenesis through the induction of c-Myc regulated cellular genes, as well as by the stimulation of cell cycle progression.