Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Department of Genetics, Cell Biology and Development, University of Minnesota, MN, USA.
Endocrinology. 2022 Aug 1;163(8). doi: 10.1210/endocr/bqac086.
Nonsurgical medical treatments are often performed for Cushing's disease due to high recurrence rates. However, current medical treatment that targets corticotroph adenomas are limited. To develop a treatment that specifically targets corticotrophs in Cushing's disease, it is necessary to identify corticotroph lineage-specific proteins, which are involved in the Cushing's tumor phenotype. We have previously reported that the expression of E2F transcription factor 1 (E2F1), one of the cell cycle regulatory proteins, was increased in corticotrophs in Cushing's disease model mice and was involved in the regulation of POMC gene expression. Phosphorylation of Ser337 of E2F1 (pS337-E2F1) facilitates its binding to the POMC promoter, which was suggested to contribute to elevated POMC expression in corticotrophs. Here, we report that E2F1 expression is specific to the corticotroph lineage in normal human pituitaries and that the E2F1 protein is localized in the cytosol in normal corticotrophs. We show that pS337-E2F1 is localized in the nucleus specifically in Cushing's tumors, while it is localized in the perinuclear cytoplasm in the normal pituitary. This observation demonstrates that pS337 is a marker for Cushing's tumors and suggests that phosphorylation of E2F1 may be a target for developing a novel pharmacological treatment for tumorigenesis and hormone dysregulation of Cushing's disease.
由于库欣病的复发率较高，通常采用非手术的医学治疗方法。然而，目前针对促肾上腺皮质激素腺瘤的医学治疗方法有限。为了开发一种专门针对库欣病促肾上腺皮质细胞的治疗方法，有必要鉴定参与库欣肿瘤表型的促肾上腺皮质细胞谱系特异性蛋白。我们之前曾报道，细胞周期调控蛋白之一的 E2F 转录因子 1（E2F1）在库欣病模型小鼠的促肾上腺皮质细胞中的表达增加，并且参与了 POMC 基因表达的调控。E2F1 的丝氨酸 337 位磷酸化（pS337-E2F1）促进其与 POMC 启动子结合，这被认为有助于促肾上腺皮质细胞中 POMC 表达的升高。在这里，我们报告 E2F1 表达在正常人类垂体中的促肾上腺皮质细胞谱系中是特异性的，并且 E2F1 蛋白在正常促肾上腺皮质细胞中定位于细胞质。我们表明 pS337-E2F1 特异性定位于库欣肿瘤的细胞核中，而在正常垂体中则定位于核周细胞质中。这一观察结果表明 pS337 是库欣肿瘤的标志物，并提示 E2F1 的磷酸化可能是开发针对库欣病肿瘤发生和激素失调的新型药物治疗的靶点。
