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).
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). 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 and 225 upregulated) (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).

Literature References

PubMed ID	Title	Journal	Year
7969139	Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator Eisen, T, Bentley, NJ, Goding, CR	Mol Cell Biol	1994
19995375	Fifteen-year quest for microphthalmia-associated transcription factor target genes Bertolotto, C, Cheli, Y, Ohanna, M, Ballotti, R	Pigment Cell Melanoma Res	2010
12730698	A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting Nitsch, R, Savaskan, NE, Kühn, H, Bräuer, AU, Ninnemann, O, Prehn, S	Nat. Neurosci.	2003
31123060	MITF-the first 25 years Arnheiter, H, Goding, CR	Genes Dev	2019
18786412	Melanocytes in development, regeneration, and cancer White, RM, Zon, LI	Cell Stem Cell	2008
8262050	Transcription activation by Myc and Max: flanking sequences target activation to a subset of CACGTG motifs in vivo Goding, CR, Gillespie, DA, Jayaraman, PS, Fisher, F, Clark, W, Crouch, DH	EMBO J	1993
30548162	Local genomic features predict the distinct and overlapping binding patterns of the bHLH-Zip family oncoproteins MITF and MYC-MAX Kawakami, A, Cheng, J, Moon, WM, Song, JS, Fisher, DE, Hejna, M	Pigment Cell Melanoma Res	2019
8164694	Melanocyte-specific gene expression: role of repression and identification of a melanocyte-specific factor, MSF Goding, CR, Yavuzer, U	Mol Cell Biol	1994
21258399	Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma Ye, T, Cormont, M, Keime, C, Kobi, D, Davidson, I, Le Gras, S, Giuliano, S, Bonet, C, Bertolotto, C, Ballotti, R, Strub, T	Oncogene	2011
9819381	Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo Goding, CR, Aksan, I	Mol Cell Biol	1998
8265351	Distinct DNA binding preferences for the c-Myc/Max and Max/Max dimers Solomon, DL, Amati, B, Land, H	Nucleic Acids Res	1993
1321344	Positive and negative elements regulate a melanocyte-specific promoter Goding, CR, Lowings, P, Yavuzer, U	Mol Cell Biol	1992
25670789	The melanocyte lineage in development and disease Jackson, IJ, Patton, EE, Mort, RL	Development	2015