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Waardenburg syndrome
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Carmen Maria Salavastru, Stefana Cretu, George Sorin Tiplica
Approximately 15% of WS type II cases are the result of mutations in the MITF gene. Individuals are heterozygotes and the mutations can be inherited in an autosomal dominant manner or occur de novo. Microphthalmia-associated transcription factor controls the development and differentiation of melanocytes, osteoclasts, and mastocytes.10,15 Mutations involving this gene lead to pigmentation loss, microphtalmia, deafness, failure of secondary bone resorption, and a small number of mast cells. The promoter of MITF-M, one of the five known isoforms of MITF, is functional only in cells of the melanocyte lineage. This promoter is upregulated by other transcription factors like PAX3 and SOX10. In addition, one of the control mechanisms for the activity and degradation of MITF-M is through c-KIT signaling.15
Pathophysiology of hyperpigmentation
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Shalini B. Reddy, Neelam A. Vashi
Several signaling pathways have been found to play a role in the synthesis, differentiation, and survival of melanocytes. Microphthalmia-associated transcription factor (MITF) is a key transcription factor in upregulating the expression of tyrosinase and stimulating melanogenesis.19,20 It also aids in the transport of melanosomes to the dendritic tips in preparation for transfer to keratinocytes.21 The expression of MITF is mainly controlled by the MSH/cAMP and KIT signaling pathways. α-MSH and adrenocorticotropic hormone (ACTH) bind to the melanocortin-1 receptor (MC1R) on the surface of melanocytes. Activated MC1R in turn activates adenylate cyclace via G protein–coupled activation, increasing intracellular cAMP levels and cAMP-responsive element-binding protein (CREB) transcription factor family members. CREB, along with other key transcription factors, including SOX10 and PAX3, is responsible for upregulation of MITF expression.6,22 Of note, α-MSH also increases melanin biosynthesis directly by removing a tyrosinase inhibitor.6 When combined with UV radiation, α-MSH has been shown to have a potentiating effect on melanogenesis.2
Overview of Molecular Pathways in Melanoma
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Microphthalmia-associated transcription factor (MITF) is essential for melanocyte development and melanin production (83). Various signaling pathways and transcription factors exert control over MITF gene and protein expression, including c-KIT-MAPK, Wnt/β-catenin, α-MSH-MC1R, PAX3, and SOX10 (83). On the basis of evidence of amplification in primary and metastatic melanomas as well as the ability to transform melanocytes in conjunction with V600E BRAF, MITF is proposed as a melanoma oncogene (84). Additionally, increased MITF copy number in cell lines appeared to correlate with resistance to cytotoxic chemotherapy. The data regarding MITF and its role in melanocyte and melanoma biology will be examined in a subsequent chapter. At this time, therapeutic interference with the MITF pathway is not possible.
Scavenger receptor A in immunity and autoimmune diseases: Compelling evidence for targeted therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Yang Xie, Yuan Jia, Zhanguo Li, Fanlei Hu
RA is a chronic autoimmune disease with joint destruction and bone damage. Several studies have shown the role of SR-A in osteoclast formation and bone destruction. Compared to WT mice, SR-A−/− mice had increased bone mass, bone thickness, bone density, and trabeculae number. Moreover, the number of osteoclasts was reduced by 60% in female SR-A−/− mice and 35% in male SR-A−/− mice, which suggested the role of SR-A in bone metabolism and osteoclast differentiation [78]. Further study by Takemura et al. confirmed these observations and found that SR-A could promote osteoclast differentiation by activating receptor activator nuclear factor kappa B (RANK) and RANK-related differentiation molecules, such as microphthalmia-associated transcription factor (MITF) and nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) [79,80]. In addition, using the murine tooth movement model (TM) and the murine anterior cruciate ligament transection model of osteoarthritis (ACLT OA), SR-A was found to activate the ERK and JNK signaling pathways and increase IL-6 expression to further stimulate the formation of osteoclasts [81].
Growth differentiation factor 15 and its role in carcinogenesis: an update
Published in Growth Factors, 2019
Anupama Modi, Shailender Dwivedi, Dipayan Roy, Manoj Khokhar, Purvi Purohit, Jeewanram Vishnoi, Puneet Pareek, Shailja Sharma, Praveen Sharma, Sanjeev Misra
Uveal melanoma patients with clinically detectable metastases had significantly higher serum GDF-15 levels (Suesskind et al. 2012), which showed experimental validation by strong expression in malignant melanoma cell lines as well as biopsies, suggesting a role of GDF-15 in metastasis (Boyle et al. 2009; Huh et al. 2010). A shRNA-mediated inhibition of GDF-15 reduced the tumorigenicity of three melanoma cell lines (D04, A2058, C32), and this was further validated in mouse xenograft models (Boyle et al. 2009). The mechanism behind GDF-15 expression in melanoma cell lines was explained by use of broad-spectrum protein kinase inhibitor staurosporine as well as specific MAPK/ERK inhibitors UO126 and PD098059, which reduced GDF-15 expression in five melanoma cell lines, suggesting the activation of MAPK pathway controls GDF-15 expression (Boyle et al. 2009). Further validation was done by siRNA-mediated targeting of V600EB-raf in two cell lines UACC903 and A375M, which illustrated that reduced V600EB-raf protein levels decreased GDF15 expression (Huh et al. 2010). Melanoma differentiation is regulated by Microphthalmia-associated Transcription Factor (MITF) and melanoma cell lines with decreased MITF levels correlated with reduced GDF-15 expression (Boyle et al. 2009). Thus, GDF-15 possibly affected the melanoma differentiation via MITF.
Topical 3% tranexamic acid enhances the efficacy of 1064-nm Q-switched neodymium-doped yttrium aluminum garnet laser in the treatment of melasma
Published in Journal of Cosmetic and Laser Therapy, 2018
Variya Laothaworn, Premjit Juntongjin
TA is currently known as an alternative medication used in melasma cases. TA works by inhibiting the conversion of plasminogen to plasmin through its attachment to lysine-binding sites of both plasmin and plasminogen. Since plasminogen also exists in keratinocytes and is involved in keratinocyte functions and interactions, TA could prevent the binding of plasminogen to keratinocytes and thereby inhibit the production of arachidonic acid and alpha-melanocyte-stimulating hormone, which are known to activate melanin synthesis (9). Moreover, TA showed a reduction in melanin pigment and tyrosinase function, including the decrease of tyrosinase-related protein (TRP) −1, TRP-2, and tyrosinase proteins. These mechanisms are activated through a process of melanogenesis, which leads to the degradation of microphthalmia-associated transcription factor (15).