Emerging roles and regulation of MiT/TFE transcriptional factors

Abstract

The MiT/TFE transcription factors play a pivotal role in the regulation of autophagy and lysosomal biogenesis. The subcellular localization and activity of MiT/TFE proteins are primarily regulated through phosphorylation. And the phosphorylated protein is retained in the cytoplasm and subsequently translocates to the nucleus upon dephosphorylation, where it stimulates the expression of hundreds of genes, leading to lysosomal biogenesis and autophagy induction. The transcription factor-mediated lysosome-to-nucleus signaling can be directly controlled by several signaling molecules involved in the mTORC1, PKC, and AKT pathways. MiT/TFE family members have attracted much attention owing to their intracellular clearance of pathogenic factors in numerous diseases. Recently, multiple studies have also revealed the MiT/TFE proteins as master regulators of cellular metabolic reprogramming, converging on autophagic and lysosomal function and playing a critical role in cancer, suggesting that novel therapeutic strategies could be based on the modulation of MiT/TFE family member activity. Here, we present an overview of the latest research on MiT/TFE transcriptional factors and their potential mechanisms in cancer.

Renal manifestation of tuberous sclerosis complex

“…These lesions also express smooth muscle actin and melanocyte markers such as gp100, a splice variant of Pmel17, and even melanin A. Expression of these melanocyte‐associated genes likely results from the mTORC1 mediated increase in MITF/TFE family transcription factor activity (Yang et al, ). This increased MITF/TFE transcription factor activity has caused confusion between TSC‐associated PEComas and the much more aggressive renal cell carcinomas (RCCs) and PEComas associated with translocations involving TFE3 or TFEB (Argani et al, ; Calcagni et al, ).…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…A prerequisite for fulfilling these distinct functions relates to their shuttling between the surface of lysosomes, the cytoplasm, and the nucleus in response to nutrient fluctuations and various forms of cellular stress. Shuttling depends on changes in the phosphorylation of multiple conserved amino acids, phosphorylation being mainly promoted by mTOR, ERK, GSK3, and AKT, and dephosphorylation by calcineurin (555,556). Furthermore, in contrast to most nontransformed tissue, tumor cells engage in de novo FA synthesis under hypoxic conditions (517,557).…”

Mitophagy Regulation in Skeletal Muscle: Effect of Endurance Exercise and Age

“…These include TFEB, TFE3, MITF and TFEC [51,53], and all share a basic motif, required for DNA binding, and a similar HLH-LZ region that is important for their dimerization. Recent evidence has identified TFEB and TFE3 as the main regulators of lysosomal homeostasis and autophagy induction within this transcriptional family [53,62].…”

“…TFEB and TFE3 directly bind to CLEAR elements, thus activating the expression of the entire network of genes that contains the CLEAR regulatory motif in their promoters [53,62]. Therefore, it is not surprising that TFEB and TFE3 overexpression results in an increased number of lysosomes and lysosomal enzymes which serve to enhance catabolic activity [53,62]. In contrast, the depletion of these transcription factors abolishes the enhanced expression of lysosomal genes.…”