User guide to MiT‐TFE isoforms and post‐translational modifications

Vu, Hong Nhung; Dilshat, Ramile; Fock, Valerie; Steingrı́msson, Eirı́kur

doi:10.1111/pcmr.12922

Cited by 18 publications

(10 citation statements)

References 111 publications

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“…In this regard, these MITF fusions are analogous to previously described cytogenetic fusions involving TFE3 and TFEB, which also preserve the bHLH-LZ domains. 4,8 The 5-prime aspect of the fusion genes is provided by the first 3 exons of either ACTB or ACTG1. It is unclear whether these actin coding sequences contribute to the functional activity of the fusion protein.…”

Section: Discussionmentioning

confidence: 99%

Clear Cell Tumor With Melanocytic Differentiation and ACTIN-MITF Translocation

Fouchardière

Pissaloux

Tirode

et al. 2020

American Journal of Surgical Pathology

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Clear cell morphology is an uncommon finding in tumors. A subset of clear cell neoplasms also shows melanocytic differentiation, including clear cell sarcoma, PEComa, and some subtypes of renal cell carcinoma. A hallmark of these tumor types is the activation of a member of the MIT/TFE family of transcription factors, which includes MITF, TFE3, TFEB, and TFEC. Microphthalmia transcription factor (MITF is the master regulator of melanin synthesis, while TFEB plays a critical role in lysosome biogenesis. Cytogenetic translocations involving TFE3 and TFEB are now well described in multiple tumor types, but there has been little evidence to suggest similar regulation of MITF. Here we describe a series of 7 clear cell cutaneous neoplasms with melanocytic differentiation that are characterized by ACTIN-MITF gene fusions, either ACTB-MITF or ACTG1-MITF. The chromosomal breakpoints preserve MITF’s dimerization and transcriptional activation domains, suggesting that these fusion proteins likely result in hyperactive MITF function, analogously to the previously reported TFE3 and TFEB fusions. Our findings indicate that MITF gene rearrangements may be key drivers of tumor pathogenesis and expand the spectrum of neoplasia associated with the MIT/TFE family.

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Section: Discussionmentioning

confidence: 99%

Clear Cell Tumor With Melanocytic Differentiation and ACTIN-MITF Translocation

Fouchardière

Pissaloux

Tirode

et al. 2020

American Journal of Surgical Pathology

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“…Melanocyte‐inducing transcription factor (MITF) operates as the master regulator of pigmentation and drives the expression of tyrosinase, gp100, and other key genes involved in melanogenesis (Hida et al , 2020; Rachmin et al , 2020; Arora et al , 2021; Vu et al , 2021; Yardman‐Frank & Fisher, 2021; Zhou et al , 2021), also in human HFs (Nishimura et al , 2005; Gáspár et al , 2011; Samuelov et al , 2013; Hardman et al , 2015). In vitro , mTORC1 functions as an important regulator of MITF activity (Ohguchi et al , 2005; Ho et al , 2011; Yun et al , 2016; Slade & Pulinilkunnil, 2017; Napolitano et al , 2022).…”

Section: Resultsmentioning

confidence: 99%

mTORC1 activity negatively regulates human hair follicle growth and pigmentation

et al. 2023

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Dysregulation of the activity of the mechanistic target of rapamycin complex 1 (mTORC1) is commonly linked to aging, cancer, and genetic disorders such as tuberous sclerosis (TS), a rare neurodevelopmental multisystemic disease characterized by benign tumors, seizures, and intellectual disability. Although patches of white hair on the scalp (poliosis) are considered as early signs of TS, the underlying molecular mechanisms and potential involvement of mTORC1 in hair depigmentation remain unclear. Here, we have used healthy, organ‐cultured human scalp hair follicles (HFs) to interrogate the role of mTORC1 in a prototypic human (mini‐)organ. Gray/white HFs exhibit high mTORC1 activity, while mTORC1 inhibition by rapamycin stimulated HF growth and pigmentation, even in gray/white HFs that still contained some surviving melanocytes. Mechanistically, this occurred via increased intrafollicular production of the melanotropic hormone, α‐MSH. In contrast, knockdown of intrafollicular TSC2, a negative regulator of mTORC1, significantly reduced HF pigmentation. Our findings introduce mTORC1 activity as an important negative regulator of human HF growth and pigmentation and suggest that pharmacological mTORC1 inhibition could become a novel strategy in the management of hair loss and depigmentation disorders.

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“…Recent papers suggest that the MiTF/TFE family serves an important role in organelle biogenesis, nutrient sensing, and energy metabolism [ 13 ]. Similar to all transcription factors, MITF governs multiple biological processes in the proliferation, cell survival, and differentiation of several types of cells with transcriptional collaborators [ 1 , 14 ]. MITF can target numerous post-translational modifications, including serine and tyrosine phosphorylation, ubiquitination, and SUMOylation [ 1 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Similar to all transcription factors, MITF governs multiple biological processes in the proliferation, cell survival, and differentiation of several types of cells with transcriptional collaborators [ 1 , 14 ]. MITF can target numerous post-translational modifications, including serine and tyrosine phosphorylation, ubiquitination, and SUMOylation [ 1 , 14 ]. Given the wide range of these biological processes, FIR-mediated phosphorylation of MITF at Ser 73 and of Akt at Ser 473 may be the starting point of signaling pathways to enhance BMSC function, including the subcellular localization, levels, and activity of MITF to activate transcriptional program.…”

Section: Discussionmentioning

confidence: 99%