Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
EMBO J. 2011 Nov 16;30(22):4571-85. doi: 10.1038/emboj.2011.325.
While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch-dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation-related genes, while it is not required for induction of 'canonical' Notch targets like p21(WAF1/Cip1), Hes1 and Hey1. Down-modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo, promoting ras-induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression.
尽管 Notch 信号在角质细胞中的促分化和抑肿瘤功能已得到充分证实，但其中的潜在机制仍知之甚少。我们在此报告，干扰素调节因子 6（IRF6）是表皮发育所必需的一个 IRF 家族成员，通过 Notch 依赖性机制在分化过程中被诱导，并作为角质细胞和角质细胞衍生的 SCC 细胞中的主要 Notch 靶标。IRF6 表达的增加有助于 Notch 激活对生长/分化相关基因的影响，而对诱导“经典”Notch 靶标如 p21(WAF1/Cip1)、Hes1 和 Hey1 则不是必需的。IRF6 的下调可拮抗体外和体内原代人角质细胞的分化，促进 ras 诱导的肿瘤形成。Notch1 和 IRF6 与表皮生长因子受体在一组临床 SCC 中的表达模式截然相反，其分化程度也不同，这说明了这些发现的临床相关性。因此，IRF6 是角质细胞中的主要 Notch 靶标，它有助于该途径在分化和肿瘤抑制中的作用。
