Omomyc expression in skin prevents Myc-induced papillomatosis
Omomyc expression in skin prevents Myc-induced papillomatosis
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DOI：
10.1038/sj.cdd.4401443
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发表时间：
2004-09-01
影响因子：
12.4
通讯作者：
Evan, GI
中科院分区：
文献类型：
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作者：
Soucek, L;Nasi, S;Evan, GI
专性致敏细胞凋亡提供了一个保护机制，对致癌潜力的Myc。Omomyc是一种突变的bHLHZip结构域，其将Myc螯合在复合物中，所述复合物不能结合E盒识别元件并激活转录，但仍能进行转录抑制。Omomyc具有逆转Myc诱导的组织培养细胞转化和增强Myc促凋亡功能的独特性质。因此，Omomyc具有作为Myc诱导的肿瘤发生的有效抑制剂的潜力。为了验证Omomyc在体内的治疗潜力，我们将其表达靶向于Inv-c-MycER（TAM）转基因小鼠的成人基底上表皮，所述转基因小鼠在基底上细胞中表达可转换形式的Myc蛋白。Myc的激活诱导表皮快速增生和乳头状瘤病。我们表明，Omomyc抑制这种Myc诱导的乳头状瘤病，增强Myc依赖性细胞凋亡的组织中，它通常是强烈抑制。此外，Omomyc表达恢复正常的角质形成细胞分化程序和皮肤结构，否则这两者都被Myc激活破坏。这些发现表明，有可能选择性地增强Myc介导的内在凋亡途径，从而抑制其致癌作用。
Obligate sensitization to apoptosis provides a safeguard mechanism against the oncogenic potential of Myc. Omomyc is a mutant bHLHZip domain that sequesters Myc in complexes that are unable to bind to the E box recognition element and activate transcription but remain competent for transcriptional repression. Omomyc has the peculiar properties of reverting Myc-induced transformation of tissue culture cells and enhancing Myc proapoptotic function. Thus, Omomyc has the potential to act as a potent suppressor of Myc-induced oncogenesis. To validate the therapeutic potential of Omomyc in vivo, we targeted its expression to the adult suprabasal epidermis of Inv-c-MycER(TAM) transgenic mice which express a switchable form of the Myc protein in suprabasal cells. Activation of Myc induces rapid epidermal hyperplasia and papillomatosis. We show that Omomyc inhibits such Myc-induced papillomatosis, potentiating Myc-dependent apoptosis in a tissue in which it is usually strongly suppressed. Furthermore, Omomyc expression restores the normal keratinocyte differentiation program and skin architecture, both of which are otherwise disrupted by Myc activation. These findings indicate that it is possible to selectively enhance the intrinsic apoptotic pathway mediated by Myc and so quell its oncogenic action.