MITF and TFEB cross-regulation in melanoma cells.

Josué Ballesteros-Álvarez,Lionel Larue,Margrét Helga Ögmundsdóttir,Valerie Fock,Katrín Möller,Ludwig Karl,Ramile Dilshat,Eiríkur Steingrímsson

doi:10.1371/journal.pone.0238546

Josué Ballesteros-Álvarez, Lionel Larue + Show 6 more

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https://doi.org/10.1371/journal.pone.0238546

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The MITF, TFEB, TFE3 and TFEC (MiT-TFE) proteins belong to the basic helix-loop-helix family of leucine zipper transcription factors. MITF is crucial for melanocyte development and differentiation, and has been termed a lineage-specific oncogene in melanoma. The three related proteins MITF, TFEB and TFE3 have been shown to be involved in the biogenesis and function of lysosomes and autophagosomes, regulating cellular clearance pathways. Here we investigated the cross-regulatory relationship of MITF and TFEB in melanoma cells. Like MITF, the TFEB and TFE3 genes are expressed in melanoma cells as well as in melanoma tumors, albeit at lower levels. We show that the MITF and TFEB proteins, but not TFE3, directly affect each other's mRNA and protein expression. In addition, the subcellular localization of MITF and TFEB is subject to regulation by the mTOR signaling pathway, which impacts their cross-regulatory relationship at the transcriptional level. Our work shows that the relationship between MITF and TFEB is multifaceted and that the cross-regulatory interactions of these factors need to be taken into account when considering pathways regulated by these proteins.

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The microphthalmia-associated transcription factor (MITF) was discovered as the gene mutated in mice carrying the coat color mutation microphthalmia (Mitf) [1]
In the 501Mel and Skmel28 human melanoma cell lines used in this study, MITF is highly expressed whereas transcription factor EB (TFEB) and TFE3 are expressed at considerably lower levels
The expression level of transcription factors may not be directly related to their importance, we decided to focus on MITF, TFEB and TFE3 in the remaining analysis

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Introduction

The microphthalmia-associated transcription factor (MITF) was discovered as the gene mutated in mice carrying the coat color mutation microphthalmia (Mitf) [1]. Mitf mutant mice lack melanocytes, resulting in pigmentation defects and deafness, and they have small eyes and some alleles show osteopetrosis (reviewed in [2]). MITF mutations have been linked to the rare dominant pigmentation disorders Waardenburg Syndrome type 2A (WS2A) [3,4] and Tietz Syndrome (TS) [5] as well as the more serious COMMAD syndrome in compound heterozygotes [6]. The MITF germline mutation E318K, has been.

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