Reactome | MITF-M-dependent gene expression

MITF-M-dependent gene expression

Stable Identifier

R-HSA-9856651

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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MITF-M is a transcriptional regulator that is critical for the establishment of melanocyte fate during embryogenesis. Key targets include the enzymes responsible for the synthesis of the pigment compounds eumelanin and pheomelanin, as well as a number of structural components of the melanosome. In addition to regulating expression of genes involved in pigmentation, MITF has also been shown to play a role in the expression of genes involved in more diverse biological processes, including proliferation, survival, lysosome biogenesis, autophagy, metabolism, DNA damage, senescence and invasion (reviewed in Goding and Arnheiter, 2019; Mort et al, 2015; Zon and White, 2008, Cheli et al, 2010). Although widely characterized as a transcriptional activator, MITF-M has also be shown to act as a transcriptional repressor, negatively regulating the expression of genes involved in extracellular matrix organization, focal adhesion and epithelial-to-mesenchymal transition (Dilshat et al, 2021; reviewed in Rambow et al, 2019).
MITF is a basic helix loop helix leucine zipper (BHLH-ZIP)-containing protein and binds DNA as a dimer - either as a homodimer or as a heterodimer with the related transcription factors TFEB, TFE3, and TFEC. TFEB and TFE3 are both widely expressed, but TFEC displays more restricted expression. In this pathway, for simplicity, MITF is shown binding DNA exclusively as a homodimer (reviewed in Goding and Arnheiter, 2019).
MITF and related BHLH protein family members bind to an E-box-like element with sequence CANNTG. Specificity of binding is determined both by the flanking nucleotides and by the identity of the two internal nucleotides of the E-box element. MITF binds preferentially to sequences CATGTG or CACGTG, and binds with less affinity to the CAGCTG sequences preferred by other BHLH proteins such as AP4 (Lowing et al, 1992; Bentley et al, 1994; Yavuzer and Goding, 1994). High-affinity MITF-binding sites also show an enrichment for flanking 5'T and 3'A, further distinguishing these sites from those preferentially bound by transcription factors such as MYC and MAX (Aksan and Goding, 1998; Fisher et al, 1993; Solomon et al, 1993; Hejna et al, 2018). Variants of high-affinity MITF binding sites present in the promoters of pigmentation genes are called M-boxes, to distinguish them from related E-box sequences (reviewed in Goding and Arnheiter, 2019). Direct targets of MITF-M have been identified by ChIP-seq and CUT-and-RUN analysis in a number of primary and melanoma cell lines (Strub et al, 2011; Webster et al, 2014; Dilshat et al, 2021). In one of these studies, high-throughput ChIP-seq in the human melanoma cell line 501Mel identified MITF-binding at 5578 potential target genes, with 2771 showing promoter-proximal binding; only a subset of these genes were shown to be directly regulated by MITF, however (465; 240 down-regulated upon MITF knockdown, and 225 upregulated upon MITF overexpression) (Strub et al, 2001; reviewed in Goding and Arnheiter, 2019). MITF-bound genes included those involved in melanocyte biogenesis as well as DNA replication, repair and mitosis (Strub et al, 2011). Other studies have identified roles for MITF-M as a direct repressor of a number of genes implicated in estracellular matrix organization, cell adhesion, invasion and epithelial-to-mesenchymal transition (Laurette et al, 2015; Dilshat et al, 2021; reviewed Rambow et al, 2019).

Literature References

PubMed ID	Title	Journal	Year
25670789	The melanocyte lineage in development and disease Mort, RL, Jackson, IJ, Patton, EE	Development	2015
31575676	Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities Rambow, F, Marine, JC, Goding, CR	Genes Dev	2019
1321344	Positive and negative elements regulate a melanocyte-specific promoter Lowings, P, Yavuzer, U, Goding, CR	Mol Cell Biol	1992
8265351	Distinct DNA binding preferences for the c-Myc/Max and Max/Max dimers Solomon, DL, Amati, B, Land, H	Nucleic Acids Res	1993
9819381	Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo Aksan, I, Goding, CR	Mol Cell Biol	1998
24443471	Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition Webster, DE, Barajas, B, Bussat, RT, Yan, KJ, Neela, PH, Flockhart, RJ, Kovalski, J, Zehnder, A, Khavari, PA	Genome Res	2014
21258399	Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma Strub, T, Giuliano, S, Ye, T, Bonet, C, Keime, C, Kobi, D, Le Gras, S, Cormont, M, Ballotti, R, Bertolotto, C, Davidson, I	Oncogene	2011
8164694	Melanocyte-specific gene expression: role of repression and identification of a melanocyte-specific factor, MSF Yavuzer, U, Goding, CR	Mol Cell Biol	1994
30548162	Local genomic features predict the distinct and overlapping binding patterns of the bHLH-Zip family oncoproteins MITF and MYC-MAX Hejna, M, Moon, WM, Cheng, J, Kawakami, A, Fisher, DE, Song, JS	Pigment Cell Melanoma Res	2019
8262050	Transcription activation by Myc and Max: flanking sequences target activation to a subset of CACGTG motifs in vivo Fisher, F, Crouch, DH, Jayaraman, PS, Clark, W, Gillespie, DA, Goding, CR	EMBO J	1993
18786412	Melanocytes in development, regeneration, and cancer White, RM, Zon, LI	Cell Stem Cell	2008
31123060	MITF-the first 25 years Goding, CR, Arnheiter, H	Genes Dev	2019
12730698	A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting Bräuer, AU, Savaskan, NE, Kühn, H, Prehn, S, Ninnemann, O, Nitsch, R	Nat. Neurosci.	2003
19995375	Fifteen-year quest for microphthalmia-associated transcription factor target genes Cheli, Y, Ohanna, M, Ballotti, R, Bertolotto, C	Pigment Cell Melanoma Res	2010
33438577	MITF reprograms the extracellular matrix and focal adhesion in melanoma Dilshat, R, Fock, V, Kenny, C, Gerritsen, I, Lasseur, RMJ, Travnickova, J, Eichhoff, OM, Cerny, P, Möller, K, Sigurbjornsdottir, S, Kirty, K, Einarsdottir, BO, Cheng, PF, Levesque, M, Cornell, RA, Patton, EE, Larue, L, de Tayrac, M, Magnusdottir, E, Ogmundsdottir, MH, Steingrímsson, E	Elife	2021
7969139	Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator Bentley, NJ, Eisen, T, Goding, CR	Mol Cell Biol	1994