MC1R 是黑色素细胞中 UV 暴露后 PTEN 的有效调节剂。
MC1R is a potent regulator of PTEN after UV exposure in melanocytes.
机构信息
Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118, USA.
出版信息
Mol Cell. 2013 Aug 22;51(4):409-22. doi: 10.1016/j.molcel.2013.08.010.
Abstract
The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.
摘要
携带黑色素皮质素受体 (MC1R) 变体的个体，尤其是那些与红发、白皙皮肤和较差的晒黑能力（RHC 特征）相关的个体，更容易患黑色素瘤；然而，其潜在机制尚不清楚。在这里，我们报告说，UVB 暴露会触发磷酸酶和张力蛋白同源物 (PTEN) 与野生型 (WT) 而非与 RHC 相关的 MC1R 变体相互作用，从而保护 PTEN 免受 WWP2 介导的降解，导致 AKT 失活。引人注目的是，MC1R 变体未能抑制 PI3K/AKT 信号的生物学后果高度依赖于上下文。在原代黑素细胞中，PI3K/AKT 信号的过度激活会导致过早衰老；在存在 BRAF(V600E) 的情况下，MC1R 缺陷诱导的升高的 PI3K/AKT 信号驱动致癌转化。这些研究确立了 MC1R-PTEN 轴作为黑色素细胞对 UVB 暴露反应的中央调节剂，并揭示了 MC1R 变体与黑色素瘤发生之间关联的分子基础。
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本文引用的文献
1
An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background.红发/白皙皮肤背景下黑色素瘤发生的紫外线辐射非依赖性途径。
Nature. 2012 Nov 15;491(7424):449-53. doi: 10.1038/nature11624. Epub 2012 Oct 31.
2
Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development.种系黑素皮质素 1 受体基因型与先天性黑素细胞痣皮肤表型严重程度相关：MC1R 在人类胎儿发育中的作用。
J Invest Dermatol. 2012 Aug;132(8):2026-32. doi: 10.1038/jid.2012.95. Epub 2012 May 10.
3
Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis.PI3K 通路激活消除 BRAFV600E 诱导的衰老有助于黑色素瘤发生。
Genes Dev. 2012 May 15;26(10):1055-69. doi: 10.1101/gad.187252.112. Epub 2012 May 1.
4
The functions and regulation of the PTEN tumour suppressor.PTEN 肿瘤抑制因子的功能与调节。
Nat Rev Mol Cell Biol. 2012 Apr 4;13(5):283-96. doi: 10.1038/nrm3330.
5
Oncogene-induced senescence and melanoma: where do we stand?癌基因诱导的衰老与黑色素瘤：我们处于何种状态？
Pigment Cell Melanoma Res. 2011 Dec;24(6):1107-11. doi: 10.1111/j.1755-148X.2011.00933.x.
6
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J Cell Physiol. 2012 Jun;227(6):2578-85. doi: 10.1002/jcp.22996.
7
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Cancer Res. 2011 Aug 1;71(15):5287-95. doi: 10.1158/0008-5472.CAN-10-4614. Epub 2011 Jul 19.
8
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Nat Cell Biol. 2011 Jun;13(6):728-33. doi: 10.1038/ncb2240. Epub 2011 May 1.
9
PTEN loss in the continuum of common cancers, rare syndromes and mouse models.PTEN 缺失在常见癌症、罕见综合征和小鼠模型的连续体中。
Nat Rev Cancer. 2011 Apr;11(4):289-301. doi: 10.1038/nrc3037.
10
Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma.PLX4032 选择性抑制 BRAF 治疗恶性黑色素瘤的疗效信号药效学特征。
Neoplasia. 2010 Aug;12(8):637-49. doi: 10.1593/neo.10414.
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