Abstract
Melanogenesis is the process of melanin synthesis through keratinocytes-melanocytes interaction, which is triggered by the damaging effect of ultraviolet-B (UVB) rays. It is known that melanogenesis influences diverse cellular responses, including cell survival and apoptosis, via complex mechanisms of feedback and crosstalk. Therefore, an attempt to suppress melanin production by modulating the melanogenesis pathway may induce perturbations in the apoptotic balance of the cells in response to UVB irradiation, which results in various skin diseases such as melasma, vitiligo, and skin cancer. To identify such appropriate target strategies for the reduction of UVB-induced melanin synthesis, we reconstructed the melanogenesis signaling network and developed a Boolean network model. Mathematical simulations of the melanogenesis network model revealed that the inhibition of beta-catenin in the melanocytes effectively reduce melanin production while having minimal influence on the apoptotic balance of the cells. Exposing cells to a beta-catenin inhibitor decreased pigmentation but did not significantly change the B-cell Chronic lymphocytic leukemia/lymphoma 2 expression, a potent regulator of apoptotic balance. Thus, our systems analysis suggests that the inhibition of beta-catenin may be the most appropriate target strategy for the reduction of UVB-induced skin pigmentation.
Highlights
Melanogenesis is the process of melanin synthesis through keratinocytes-melanocytes interaction, which is triggered by the damaging effect of ultraviolet-B (UVB) rays
Melanogenesis, the process of skin color formation, is controlled by a complex molecular regulatory network embedded in the keratinocytes and melanocytes, which results in the skin and hair pigmentation[1,2,3]
These keratinocytes-derived factors are transported to melanocytes in a paracrine manner and induce Microphthalmia-associated transcription factor (MITF) activation through a series of signaling events, which results in melanin production via activation of tyrosinase-related proteins[1,2,3]
Summary
Melanogenesis is the process of melanin synthesis through keratinocytes-melanocytes interaction, which is triggered by the damaging effect of ultraviolet-B (UVB) rays. An attempt to suppress melanin production by modulating the melanogenesis pathway may induce perturbations in the apoptotic balance of the cells in response to UVB irradiation, which results in various skin diseases such as melasma, vitiligo, and skin cancer To identify such appropriate target strategies for the reduction of UVB-induced melanin synthesis, we reconstructed the melanogenesis signaling network and developed a Boolean network model. An attempt of skin color control by modulating the melanogenesis pathway may induce perturbations in the apoptotic balance of the cells, which can cause various skin diseases such as melasma, vitiligo, and skin cancer[3,5,6,7] To overcome such biological complexity and investigate appropriate target strategy for the reduction of UVB-induced skin pigmentation, we have developed a novel and comprehensive mathematical model of the melanogenesis network by integrating all available experimental results that are closely associated with the melanin synthesis under UVB irradiation. Our findings highlight the significance of network-level analyses for understanding bio-molecular regulatory mechanisms, and finding an optimal target and its intervention strategy to reduce UVB-induced melanin synthesis
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