mTORC1 激活可阻断 BrafV600E 诱导的生长停滞，但不足以形成黑色素瘤。
mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation.
机构信息
Department of Dermatology, Yale University, New Haven, CT 06510, USA.
Department of Dermatology, Yale University, New Haven, CT 06510, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
出版信息
Cancer Cell. 2015 Jan 12;27(1):41-56. doi: 10.1016/j.ccell.2014.11.014.
Braf(V600E) induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf(V600E) melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth arrest of Braf(V600E) melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis.
Braf(V600E) 可诱导良性、生长停滞的黑素细胞痣发育，但也可驱动黑色素瘤形成。在 Braf(V600E)黑素细胞中缺失 Cdkn2a 会导致罕见的黑色素瘤进展，但仅在稳定的生长停滞为痣后才会发生。miR-99/100 的上调可防止黑色素瘤的即刻进展，其下调 mTOR 和 IGF1R 信号。Stk11 (Lkb1) 缺失导致 mTORC1 的激活可消除 Braf(V600E)黑素细胞痣的生长停滞，但不足以完全进展为黑色素瘤。Cdkn2a 缺失与人类和鼠类黑素细胞肿瘤中的 mTORC2 和 Akt 激活有关。Braf(V600E)黑素细胞中同时缺失 Cdkn2a 和 Lkb1 会导致 mTORC1 和 mTORC2/Akt 的激活，从而在小鼠中迅速诱导黑色素瘤形成。在该模型中，mTORC1/2 的激活均是 Braf 诱导的黑色素瘤发生所必需的。
Zotero 插件