摘要
Trib1, Trib2, and Trib3 are mammalian homologues of the Tribbles protein family, an evolutionarily conserved group of proteins that can mediate proteasome-dependent degradation. Evidence suggests that these proteins function as adapters, where they recruit E3 ligases and enhance ubiquination of the target protein in order to promote its degradation. To date, increased Trib1 and Trib2 mRNA expression has been shown to correlate with acute myelogenous leukemia (AML) in humans and induces AML in mice; whereas Trib3 has not been associated with AML. In order to understand the effects of Trib family members in hematopoietic cells, we reconstituted mice with hematopoietic progenitors retrovirally expressing Trib1, Trib2, or Trib3. Trib1 and Trib2 mice developed AML whereas Trib3 mice did not. Our previous data suggested that Trib2-mediated degradation of the transcription factor, C/EBP, is important for leukemogenesis. We now show that Trib1, like Trib2, strongly binds C/EBP and induces its degradation. In contrast, Trib3 weakly binds C/EBP and fails to induce its degradation. Consistent with the ability to strongly bind and degrade C/EBP, Trib1 and Trib2, but not Trib3, block differentiation of myeloid cells. We are currently mapping the domains that account for the differences between Trib1/Trib2 and Trib3 in leukemogenesis. Together, our results strengthen the correlation between Trib-induced C/EBP degradation and induction of AML. Furthermore, our data show that different Tribbles family members have distinct targets and understanding this specificity may provide opportunities to therapeutically target Tribbles.
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摘要译文
Trib1，TRIB2和TRIB3是符段SUP / SUP蛋白家族的哺乳动物同系物，蛋白质的进化上保守的组SUP / SUP，可介导蛋白酶体依赖的降解。证据SUP / SUP提示这些蛋白用作适配器，在那里他们SUP / SUP招募E3连接酶，增强，以促进其降解靶蛋白SUP / SUP的泛素化。至今，增加Trib1 SUP / SUP和TRIB2 mRNA的表达已被证实与急性SUP / SUP髓细胞性白血病（AML）在人类和诱导的AML小鼠;SUP / SUP而TRIB3尚未与AML有关。为了SUP / SUP了解论坛报的家庭成员在造血SUP / SUP细胞的作用，我们重组小鼠造血祖细胞SUP / SUP逆转录病毒表达Trib1，TRIB2，或TRIB3。 Trib1和TRIB2 SUP / SUP小鼠发展AML而TRIB3小鼠没有。我们以前的SUP / SUP的数据显示，TRIB2介导的转录SUP / SUP的因素，C / EBP的退化，是白血病的重要。我们现在展示SUP / SUP的Trib1，像TRIB2，强烈结合C / EBP，并诱导其SUP / SUP退化。相比之下，TRIB3弱结合C / EBP和失败SUP / SUP诱导其降解。符合能力强SUP / SUP绑定和降低C / EBP，Trib1和TRIB2，但不TRIB3，块粒细胞SUP / SUP的分化。目前，我们正在映射SUP / SUP该帐户在白血病之间的差异Trib1 / TRIB2 SUP / SUP和TRIB3域。总之，我们的结果强化SUP / SUP论坛报诱导C / EBP退化和感应SUP / SUP的AML之间的相关性。此外，我们的数据显示，不同的符段家庭SUP / SUP成员有不同的目标和理解这种特殊性SUP / SUP可以提供机会治疗目标符段。SUP / SUP脚注通讯作者SUP / SUP披露：没有利益冲突的相关申报SUP / SUP CiteULike的connotea Del.icio。我们Digg的书签交易Technorati的这是什么？
Priya Dedhia[1][*]; Karen Keeshan[2][*]; Maria Vega[1][*]; Sacha Uljon, M.D., Ph.D.[3][*]; Lanwei Xu[1][*]; Olga Shestova[1][*]; Candice Romany[1][*]; Stephen C Blacklow, M.D., Ph.D.[4][*] ;Warren S. Pear, MD, PhD[1]. Trib1 and Trib2 but Not Trib3 Degrade C/EBPá and Induce Acute Myelogenous Leukemia[J]. Blood, 2008,112(11): 2950-2950