Mammalian target of rapamycin complex 1 (mTORC1) may modulate the timing of anagen entry in mouse hair follicles

Abstract

inducing fast recruitment of MiTF into the nucleus, to activate transcription of enzymes and proteins related to melanogenesis and, at the same time, prevent MiTF degradation by lowering the level of P-ERK. Thus, the ability of IB-MECA to elevate DOPA oxidase activity, melanin synthesis and cell dendricity is in line with MiTF role in regulating melanin synthesis, melanosome transport and dendricity (23).In skin explants, IB-MECA induced an increase in melanization, when applied topically. Histological data show an increase in deposition of melanin in keratinocytes. A possible clinical application of IB-MECA can be envisaged in the treatment of hypopigmentation disorders. Thus, it may be suggested that the activation of melanocytes located in the peripheral zones of the depigmented areas, as in vitiligo (24), by IB-MECA could increase melanocyte dendricity and melanin deposition into keratinocytes in the hypopigmented lesions of the skin. AcknowledgementsWe thank the late Eliezer Flescher (Tel-Aviv University, Israel) for providing B16F1 melanoma cells and Leonid Mittelman and Alex Barbul (Tel-Aviv University) for their support in confocal and RIC microscopic measurements. Author contributionLea Madi designed and performed the research and wrote the study, Rafi Korenstein designed the research and wrote the study, Bianca RosenbergHaggen designed the ex vivo studies and Abraham Nyska performed the histopathology evaluation. Conflict of interestsLea Madi and Rafi Korenstein are inventors of a patent on modulation of skin pigmentation. Bianca Rosenberg and Abraham Nyska state no conflict of interest. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Figure S1. The effect of IB-MECA on melanogenesis of B16 melanoma cells. Figure S2. The effect of IB-MECA on cAMP level. Figure S3. The effect of IB-MECA and wortmannin on PI3K/AKT signaling pathway. Figure S4. MiTF expression and localization, following exposure of B16 -melanoma cells to IB-MECA. Figure S5. The effect of IB-MECA on DOPA oxidase activity in B16 -melanoma cells. Figure S6. Images of B16 melanoma cells exposed to dual treatment of 10 lM MECA or/and 1 lM PD98059 or each one alone on melanin contents in the cell pellets. Figure S7. Melanosomes average density in skin exposed to IB-MECA.Appendix S1. Materials and methods. D-91054 Erlangen, Germany, Tel.: +49-9131-8534311, Fax: +49-9131-8536597, e-mail: miyuki.tauchi@uk-erlangen.de Abstract: Mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation and survival. There is limited evidence that mTOR influences hair follicles (HFs), which undergo cycles of quiescence (telogen), growth (anagen) and regression (catagen). We sought to investigate whether mTOR, in particular mTOR complex 1 (mTORC1), regulates the hair growth cycle by employing biochemical, immunohistochemical and functional approaches in vivo. Here, we demonstrate that quantitative analysis of mTORC1 kinase activity shows phase-dependent changes, and phosphorylate...

Hair regeneration by small molecules that activate autophagy

“…It was previously reported that mTOR may be required for HFSC activation and anagen entry (Castilho et al, 2009;Kellenberger and Tauchi, 2013;Deng et al, 2015). However, our results above indicate that moderate inhibition of mTOR by rapamycin accompanied by autophagy induction stimulates hair regeneration.…”

“…Skin remains in telogen during this whole treatment period as confirmed by the lack of skin pigmentation. Number µM does not enhance hair regeneration (data not shown); this may be due to more severe inhibition of mTOR which was reported to be required for HFSC activation (Castilho et al, 2009;Kellenberger and Tauchi, 2013;Deng et al, 2015). Number of animals: control (15), rapamycin (12).…”

Topical application of rapamycin ointment ameliorates Dermatophagoides farina body extract‐induced atopic dermatitis in NC/Nga mice

“…It has also been demonstrated that dendritic cell migration into the draining lymph node can be influenced by rapamycin . Mammalian target of rapamycin complex 1 (mTORC1) was also reported to modulate the timing of antigen entry in mouse hair follicles . Recently, several reports have suggested the therapeutic efficacy of rapamycin for various immunological disorders.…”

Expression of decorin throughout the murine hair follicle cycle: hair cycle dependence and anagen phase prolongation

“…Skin thickness and size were evaluated by digital image analysis using Photoshop ® software, and at least 50 longitudinally cut follicles per sample were counted. Then, the hair stage percentage and the HCS were classified and assessed by histomorphometry according to the previously published hair cycle staging guidelines and morphological characteristics of the murine hair cycle . For the anagen–catagen transition study, anagen VI HFs were assigned a score of 100, HFs in early catagen (catagen II–III) received a score of 200, while HFs in mid‐ and late catagen (catagen IV–V) were assigned a score of 300.…”