Dual roles of lineage restricted transcription factors

Abstract

m i c r o p h t h a l m i a -a s s o c i a t e d transcription factor, mitf, is a master regulator of melanocyte development, differentiation, migration and survival. 1 a broad collection of studies have indicated that mitf directly regulates the transcription of genes involved in pigmentation, which are selective to the melanocyte lineage. in addition, mitf controls expression of genes which are expressed in multiple cell lineages and may also play differential roles in activating vs. maintaining gene expression patterns. in this point-of-view article, we discuss lineage restricted transcription factor activation of both tissue-specific and ubiquitously expressed genes using melanocytes and mitf as a model system that may eventually provide insights into such processes in multiple cell lineages.Cell reprogramming, where the epigenetic signature directing cellular identity can be erased and rewritten, demonstrates the pervasive and far-reaching importance of transcription factors in the development, maintenance and rewiring of cells.2 In 2006, Takahashi and Yamanaka published their seminal study on cell reprogramming, showing that only four selected transcription factors were required to directly and permanently transform adult mouse fibroblasts into induced pluripotent stem (iPS) cells.3,4 However, reprogramming can also include the conversion of one somatic cell type to another.In 1996, it was shown that ectopic expression of a single transcription factor, MITF, may convert fibroblasts into cells with characteristics of pigment-producing dual roles of lineage restricted transcription factors

Differentiated melanocyte cell division occurs in vivo and is promoted by mutations in Mitf

“…CDK2) and inhibit cell cycle progression (e.g. p21) (Levy and Fisher, 2011). In melanoma, MITF has been proposed to act as a 'rheostat': low levels of Mitf promote stem-like invasiveness, moderate levels stimulate proliferation, and high levels cause differentiation with cell cycle arrest (Hoek and Goding, 2010;Khaled et al, 2010).…”

“…We speculate that MITF 4T⌬2B uncoupling of differentiation and cell cycle arrest in development may be relevant to the oncogenesis of MITF 4T⌬2B mutant melanoma. How melanocytes fine-tune Mitf activity in a temporal-and spatial-specific manner is a complex challenge in melanocyte biology (Levy and Fisher, 2011), and includes coordination of extrinsic signals, transcriptional regulation (Levy et al, 2006), interactions with related transcription factors (Hemesath et al, 1994), chromatin modifiers (de la Serna et al, 2006;Keenen et al, 2010;Price et al, 1998;Sato et al, 1997) and direct protein interactions (Bismuth et al, 2005). Our work illustrates the importance of fine tuning Mitf activity in melanocytes because Mitf activity that is sufficient for specification and differentiation is not sufficient for cell cycle arrest.…”

IFN-γ signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation

“…Tyrosinase (Tyr), dopachrome tautomerase (Dct), and Tyr-related protein-1 (Tyrp1) are the core enzymes involved in melanin synthesis (8,9). Microphthalmia-associated transcription factor (MITF) is suggested to be the master regulator that governs melanocyte development, melanogenesis, and survival (10). The MITF promoter is further regulated by other transcription factors through an array of intrinsic regulators derived from fibroblasts, as well as endocrine, neural, and inflammatory factors (11,12).…”

Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF

“…Among the functional transcriptional targets of MITF are regulators of cell cycle (CDK2, TBX2, p21, p16/Ink4a), survival and metastasis (BCL2, c-Met), miRNA processing [Dicer (9)], cAMP levels [PDE4D3 (10)], and pigmentation (Tyrosinase, TYRP1/2, OA1), along with others including genes important to the biology of osteoclasts and mast cells (reviewed in ref. 11). Transcriptional activity of MITF requires its DNA binding to the E-box sequence CAC(G/A)TG as a homodimer or as a heterodimer with one of its related bHLH-Zip proteins TFEB, TFEC, and TFE3 (collectively referred to as the MiT family) (12).…”