Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, México.
J Mol Med (Berl). 2022 Jul;100(7):973-983. doi: 10.1007/s00109-022-02216-0. Epub 2022 Jun 7.
Coregulator proteins interact with signal-dependent transcription factors to modify their transcriptional activity. ZMIZ1 and ZMIZ2 (zinc finger MIZ-type containing 1 and 2) are coregulators with nonredundant functions that share unique structural characteristics. Among other interacting domains, they possess a MIZ (Msx-interacting zinc finger) that relates them to members of the protein inhibitor of activated STAT (PIAS) family and provides them the capacity to function as SUMO E3 ligases. The ZMIZ proteins stimulate the activity of various signaling pathways, including the androgen receptor (AR), P53, SMAD3/4, WNT/β-catenin, and NOTCH1 pathways, and interact with the BAF chromatin remodeling complex. Due to their molecular versatility, ZMIZ proteins have pleiotropic effects and thus are important for embryonic development and for human diseases. Both have been widely associated with cancer, and ZMIZ1 has been very frequently identified as a risk allele for several autoimmune conditions and other disorders. Moreover, mutations in the coding region of the ZMIZ1 gene are responsible for a severe syndromic neurodevelopmental disability. Because the actions of coregulators are highly gene-specific, a better knowledge of the associations that exist between the function of the ZMIZ coregulators and human pathologies is expected to potentiate the use of ZMIZ1 and ZMIZ2 as new drug targets for diseases such as hormone-dependent cancers.
核心调节蛋白与信号依赖性转录因子相互作用，从而改变其转录活性。ZMIZ1 和 ZMIZ2（含锌指 MIZ 型 1 和 2）是具有非冗余功能的核心调节蛋白，它们具有独特的结构特征。在其他相互作用的结构域中，它们具有 MIZ（Msx 相互作用的锌指），使它们与蛋白抑制物激活 STAT（PIAS）家族的成员相关，并使它们具有作为 SUMO E3 连接酶的功能。ZMIZ 蛋白刺激各种信号通路的活性，包括雄激素受体 (AR)、P53、SMAD3/4、WNT/β-连环蛋白和 NOTCH1 通路，并与 BAF 染色质重塑复合物相互作用。由于其分子多功能性，ZMIZ 蛋白具有多种效应，因此对胚胎发育和人类疾病非常重要。两者都与癌症广泛相关，ZMIZ1 已被广泛认为是几种自身免疫性疾病和其他疾病的风险等位基因。此外，ZMIZ1 基因编码区的突变导致严重的综合征性神经发育障碍。由于核心调节蛋白的作用具有高度的基因特异性，因此预计更好地了解 ZMIZ 核心调节蛋白的功能与人类病理学之间存在的关联，将有助于将 ZMIZ1 和 ZMIZ2 用作激素依赖性癌症等疾病的新药物靶点。
