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Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation
Juxiang Cao, … , Hans R. Widlund, David J. Kwiatkowski
Juxiang Cao, … , Hans R. Widlund, David J. Kwiatkowski
Published December 5, 2016
Citation Information: J Clin Invest. 2017;127(1):349-364. https://doi.org/10.1172/JCI84262.
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Research Article Dermatology Genetics

Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation

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Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis. Genetic suppression or pharmacological inhibition of this signaling cascade at multiple levels restored pigmentation. Importantly, primary melanocytes isolated from hypomelanotic macules from 6 patients with TSC all exhibited reduced TSC2 protein expression, and 1 culture showed biallelic mutation in TSC2, one of which was germline and the second acquired in the melanocytes of the hypomelanotic macule. These findings indicate that the TSC/mTORC1/AKT/GSK3β/β-catenin/MITF axis plays a central role in regulating melanogenesis. Interventions that enhance or diminish mTORC1 activity or other nodes in this pathway in melanocytes could potentially modulate pigment production.

Authors

Juxiang Cao, Magdalena E. Tyburczy, Joel Moss, Thomas N. Darling, Hans R. Widlund, David J. Kwiatkowski

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Figure 5

GSK3β inhibition prevents loss of pigmentation in response to TSC protein complex loss.

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GSK3β inhibition prevents loss of pigmentation in response to TSC protei...
(A) Immunoblot analysis of iHPMs expressing shTSC1 or shTSC2 or control (Scr) after treatment with the GSK3β-specific inhibitor CHIR-99021 (CHIR) (3 μM) for 5 days. Note the recovery of β-catenin and MITF expression in cells treated with CHIR-99021. (B) Entirely similar to the data shown in A, except using the GSK3β-specific inhibitor AR-A014418 (ARA) (5 μM) for 5 days. (C) Entirely similar to the data shown in A, except using the GSK3β-specific inhibitor 6-bromoindirubin-3’-oxime (BIO) (2 μM) for 5 days. (D and E) Immunoblot analysis shows recovery of nuclear β-catenin in iHPMs following treatment with CHIR-99021 and AR-A014418, respectively. (F–H) Pigmentation was restored in cells treated with CHIR-99021, AR-A014418, and BIO, respectively. The immunoblots presented in the figure include replicate samples run on parallel gels.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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