POU3F2 binds the MITF promoter

Stable Identifier
R-HSA-9858286
Type
Reaction [binding]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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POU3F2 binds the MITF promoter
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POU3F2, also known as BRN2, is a transcription factor that has roles in neuronal development and plays roles in the development of the melanocyte lineage and in the progression of melanoma downstream of the WNT, MAPK and PI3K pathways (Goodall et al, 2004a; Goodall et al, 2004b; Bonvin et al, 2012; reviewed in Fane et al, 2019; Goding and Arnheiter, 2019; Cook et al, 2008). POU3F2 has been shown to bind directly to promoter elements upstream of the MITF gene by EMSA (Herbert et al, 2019; Goodall et al, 2008). In melanoma cells, POU3F2 has been reported as both an activator and a repressor of MITF expression (Wellbrock et al, 2008; Goodall et al, 2008). The ability of POU3F2 to bind DNA may depend in part on a conformational change in the N-terminal region in response to p38-dependent phosphorylation at residues S91 and S96, providing a link through p38 to the UV stress response (Herbert et al, 2019).
The relationship of POU3F2 and MITF expression appears to be somewhat context dependent. During melanogenesis, POU3F2 is expressed in neural crest precursor cells in a manner that depends on WNT, PI3K and MAPK signaling, but is not expressed in melanocytes that express MITF (Goodall et al, 2004a, Cook et al, 2003). During melanoma progression, POU3F2 and MITF are expressed in distinct subsets of cells within a tumor (Goodall et al, 2008, Thurber et al, 2011), possibly as the result of a negative feedback loop established through the MITF target miR-211 that downregulates POU3F2 levels (Boyle et al, 2011). POU3F2 expression has a role in driving invasion of melanoma cells, and the relative levels of MITF and POU3F2 may act to regulate the proliferative versus invasive properties of these cells (reviewed in Fane et al, 2019; Goding and Arnheiter et al, 2019).
In addition to its role at the promoter of the MITF gene, POU3F2 has also been implicated in the DNA damage response (DDR) pathway in melanoma cells by virtue of its interaction with DDR factors such as DNA-dependent protein kinases DNAPK and PRKDC, PARP1 and the Ku70/Ku80 dimer (Herbert et al, 2019). The interaction of POU3F2 and Ku70/80 dimer promotes resolution of DNA damage through the mutation prone non-homologous end-joining (NHEJ) pathway rather than through homologous recombination. In this way, POU3F2 may contribute to the high mutation burden of melanoma cell lines (Herbert et al, 2019; reviewed in Goding and Arnheiter, 2019; Fane et al, 2019). However, POU3F2 also directly activates PTEN expression, while MITF represses PTEN expression and in BRAF V600E/PTEN +/- mice, POU3F2 haploinsufficiency promotes melanoma initiation and metastasis (Hamm et al, 2021)

Literature References
PubMed ID Title Journal Year
29781575 BRN2, a POUerful driver of melanoma phenotype switching and metastasis

Sturm, RA, Chhabra, Y, Fane, ME, Smith, AG

Pigment Cell Melanoma Res 2019
15024080 The Brn-2 transcription factor links activated BRAF to melanoma proliferation

Dexter, TJ, Goodall, J, Goding, CR, Wellbrock, C, Marais, R, Roberts, K

Mol Cell Biol 2004
15024079 Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin

Dexter, TJ, Champeval, D, Martinozzi, S, Carreira, S, Goodall, J, Goding, CR, Larue, L

Mol Cell Biol 2004
18628967 Oncogenic BRAF regulates melanoma proliferation through the lineage specific factor MITF

Pickersgill, H, Brummelkamp, T, Wellbrock, C, Paterson, H, Rana, S, Marais, R

PLoS One 2008
18829533 Brn-2 represses microphthalmia-associated transcription factor expression and marks a distinct subpopulation of microphthalmia-associated transcription factor-negative melanoma cells

Sturm, RA, Nuciforo, P, Davidson, I, Carreira, S, Goodall, J, Goding, CR, Denat, L, Larue, L, Kobi, D

Cancer Res 2008
18983536 POU domain transcription factors: BRN2 as a regulator of melanocytic growth and tumourigenesis

Sturm, RA, Cook, AL

Pigment Cell Melanoma Res 2008
21435193 Melanoma cell invasiveness is regulated by miR-211 suppression of the BRN2 transcription factor

Sturm, RA, Hacker, E, Boyle, GM, Dutton-Regester, K, Stark, MS, Bonazzi, VF, Cook, AL, Woods, SL, Aoude, LG, Hayward, NK

Pigment Cell Melanoma Res 2011
31123060 MITF-the first 25 years

Arnheiter, H, Goding, CR

Genes Dev 2019
21358674 Inverse expression states of the BRN2 and MITF transcription factors in melanoma spheres and tumour xenografts regulate the NOTCH pathway

Smit, DJ, Zabierowski, SE, Leonard, JH, Ramakrishnan, SN, Sturm, RA, Hacker, E, Douglas, G, Sturm, EC, Herlyn, M, Thurber, AE

Oncogene 2011
30804224 BRN2 suppresses apoptosis, reprograms DNA damage repair, and is associated with a high somatic mutation burden in melanoma

Middleton, MR, Sesma-Sanz, L, Andrews, S, Robles-Espinoza, CD, Goding, CR, Louphrasitthiphol, P, Binet, R, Larue, L, Chauhan, J, Herbert, K, Lambert, JP, Masson, JY, Roberts, ND, Suer, E, Sarkar, S, Kalkavan, H, Falletta, P, Gingras, AC

Genes Dev 2019
34140478 BRN2 is a non-canonical melanoma tumor-suppressor

Cornell, RA, Sánchez-Del-Campo, L, Petit, V, Le Coz, M, Hamm, M, Delmas, V, Goding, CR, Larue, L, Bellacosa, A, Pouteaux, M, Gesbert, F, Davidson, I, Rambow, F, Lauss, M, Sarasin, A, Meijer, D, Mosteo, L, Steingrímsson, E, Raymond, JH, Jönsson, GB, Aktary, Z, Kenny, C, Sohier, P, Charoenchon, N

Nat Commun 2021
14708619 Human melanoblasts in culture: expression of BRN2 and synergistic regulation by fibroblast growth factor-2, stem cell factor, and endothelin-3

Sturm, RA, Leonard, JH, Bennett, DC, Murphy, M, Herlyn, M, Cook, AL, Donatien, PD, Jones, MK, Smith, AG

J Invest Dermatol 2003
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Output
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Authored
Rothfels, K  (2023-12-21)
Reviewed
de la Serna, IL  (2024-05-21)
Arnheiter, H  (2024-02-26)
Created
Rothfels, K  (2024-01-10)
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