The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.
The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.
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DOI：
10.1101/gad.585710
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发表时间：
2010-06
影响因子：
10.5
通讯作者：
Jan van Riggelen;Judith M. Müller;T. Otto;Vincent Beuger;Alper Yetil;P. Choi;C. Kosan;T. Möröy;D. Felsher;M. Eilers
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文献类型：
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作者：
Jan van Riggelen;Judith M. Müller;T. Otto;Vincent Beuger;Alper Yetil;P. Choi;C. Kosan;T. Möröy;D. Felsher;M. Eilers
Myc蛋白通过与Miz 1结合抑制几种细胞周期蛋白依赖性激酶抑制剂（CKIs）的转录;这种相互作用对Myc诱导或维持肿瘤发生的能力是否重要尚不清楚。在这里，我们表明，点突变的Myc（MycV 394 D），这是选择性缺陷结合Miz 1的致癌潜力大大减弱。在T细胞淋巴瘤中，持续需要Myc与Miz 1的结合来抑制CKI表达并抑制三甲基化组蛋白H3在Lys 9（H3 K9 triMe）处的积累，这是细胞衰老的标志。出现的淋巴瘤表达大量的转化生长因子β-2（TGF β-2）和TGF β-3。在Myc抑制后，需要TGF β信号传导来诱导CKI表达和细胞衰老并抑制肿瘤复发。Myc与Miz 1的结合是拮抗TGF β的生长抑制和衰老诱导所必需的。我们证明，由于淋巴瘤表达高水平的TGF β，他们准备引发自分泌程序的Myc失活后衰老，表明TGF β是一个关键因素，建立癌基因成瘾的T细胞淋巴瘤。
The Myc protein suppresses the transcription of several cyclin-dependent kinase inhibitors (CKIs) via binding to Miz1; whether this interaction is important for Myc's ability to induce or maintain tumorigenesis is not known. Here we show that the oncogenic potential of a point mutant of Myc (MycV394D) that is selectively deficient in binding to Miz1 is greatly attenuated. Binding of Myc to Miz1 is continuously required to repress CKI expression and inhibit accumulation of trimethylated histone H3 at Lys 9 (H3K9triMe), a hallmark of cellular senescence, in T-cell lymphomas. Lymphomas that arise express high amounts of transforming growth factor beta-2 (TGFbeta-2) and TGFbeta-3. Upon Myc suppression, TGFbeta signaling is required to induce CKI expression and cellular senescence and suppress tumor recurrence. Binding of Myc to Miz1 is required to antagonize growth suppression and induction of senescence by TGFbeta. We demonstrate that, since lymphomas express high levels of TGFbeta, they are poised to elicit an autocrine program of senescence upon Myc inactivation, demonstrating that TGFbeta is a key factor that establishes oncogene addiction of T-cell lymphomas.