Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Mol Cell Biol. 2010 May;30(10):2518-36. doi: 10.1128/MCB.01308-09. Epub 2010 Mar 22.
Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G(0)/G1 and G(1)/S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.
Runx1/AML1 是一种参与组织干细胞调节的转录因子,属于癌症基因的小 Runx 家族。在毛囊(HF)中,Runx1 在形态发生中的上皮缺失会损害正常的成人毛发生长周期(循环)并阻止成人毛囊干细胞(HFSCs)处于静止状态。在这里,我们表明这些影响在成年后期会被克服。通过在形态发生结束后删除 Runx1,我们证明了它在促进毛发生长期开始和 HFSC 增殖中的直接作用。Runx1 的缺失导致细胞周期蛋白依赖性激酶抑制剂 Cdkn1a(p21)上调。干扰培养的 HFSCs 中的 Runx1 功能会损害它们的增殖和正常的 G0/G1 和 G1/S 细胞周期进程。通过添加 Runx1 或删除 p21 可以挽救增殖缺陷。在小鼠中化学诱导的皮肤肿瘤发生会导致皮肤上皮、乳头瘤和鳞状细胞癌区域的广泛 Runx1 表达。此外,它还揭示了在没有 Runx1 的情况下肿瘤形成率降低,同时上皮细胞中磷酸化 Stat3 的水平降低。正常人和小鼠的毛发生长周期中 Runx1 蛋白表达相似。我们提出,Runx1 可能通过直接促进上皮细胞的增殖而充当皮肤癌基因。