一个新的反馈调节回路——ΔNp63α/MM1/c-Myc通路在皮肤衰老中的作用及其分子机理

Both ΔNp63α and c-Myc are key transcription factors in skin development and aging. In our preliminary research, we found a novel feedback loop in which ΔNp63α regulates itself and c-Myc: ΔNp63α positively regulates c-Myc via transactivates E3 ligase HERC3 and consequently promotes degradation of c-Myc inbitor MM1, which also inhibits transcription of ΔNp63α. This ΔNp63α/MM1/c-Myc pathway is significantly downregulated in senescent mouse skin and senescence stress-induced keratinocytes and mouse skin. In this project, we plan to further investigate the functions and mechanism of ΔNp63α/MM1/c-Myc pathway in skin senescence. We are going to phenotype skin-specifically inducible transgenic mouse model of MM1, which is at the center of this pathway, and vertify whether this pathway can accelerate downregulation of ΔNp63α and c-Myc, consequently accelerating skin aging, as well as further illuminate the mechanism of this novel pathway. Our project is helpful to elucidate the molecular mechanism of skin aging.

ΔNp63α和c-Myc是皮肤发育和衰老调控中的重要转录因子。在前期研究中，我们发现了一个全新的ΔNp63α对自身和c-Myc的反馈调节回路：ΔNp63α通过激活E3泛素连接酶HERC3，促进c-Myc的抑制因子MM1降解，进而上调c-Myc；MM1反过来抑制ΔNp63α转录。这一ΔNp63α/MM1/c-Myc通路在衰老的小鼠皮肤中以及衰老压力诱导的细胞和小鼠皮肤中均有明显下调。在本项目中，我们以小鼠为模型进一步研究这一通路在皮肤衰老中的作用及其分子机理；通过在转基因小鼠中皮肤特异性诱导表达处于这一反馈调节回路中心的MM1，分析其皮肤衰老表型，验证ΔNp63α/MM1/c-Myc通路在小鼠皮肤衰老过程中是否能加速ΔNp63α和c-Myc下调、进而加速衰老进程；并对我们新发现的这一反馈调节回路的分子机理进行深入研究。本项目对于揭示皮肤衰老的分子机制具有重要意义

ΔNp63α和c-Myc是皮肤发育和衰老调控中的重要转录因子。在前期研究中，我们发现了一个全新的ΔNp63α对自身和c-Myc的反馈调节回路：ΔNp63α通过激活E3泛素连接酶HERC3转录，促进c-Myc的抑制因子MM1降解，进而上调c-Myc；MM1反过来抑制ΔNp63α转录。在本项目中，我们以小鼠和角质化细胞为模型研究ΔNp63α/MM1/c-Myc通路在皮肤衰老中的作用，结果表明：MM1在体外培养的角质化细胞和转基因小鼠以及UVB诱导的皮肤光老化模型中，通过从mRNA水平下调ΔNp63α，从而调节ΔNp63α/MM1/c-Myc回路，进而促进皮肤角质化细胞和皮肤衰老；UVB等衰老压力可能通过稳定MM1 mRNA，上调MM1蛋白水平，进而影响ΔNp63α/MM1/c-Myc回路，加速皮肤衰老。本项目对于揭示皮肤衰老的分子机制具有重要意义。