MITF-M dimer binds the CDKN1A promoter

Stable Identifier
R-HSA-9825835
Type
Reaction [binding]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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MITF-M dimer binds the CDKN1A promoter
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MITF binds to an E-box element in the promoter of the CDKN1A gene as assessed by EMSA and ChIP in melanoma cells (Carreira et al, 2005). MITF binding stimulates CDKN1A expression in an E-box-dependent manner as demonstrated by reporter gene assay (Carreira et al, 2005). The CDKN1A gene encodes the G1 cyclin-dependent kinase inhibitor p21. CDKN1A activity is upregulated in cells with high levels of overall MITF activity and promotes exit from the cell cycle and activation of the MITF-dependent differentiation program (Carreira et al, 2005).
The identification of the cell cycle inhibitor CDKN1A as an MITF target gene is somewhat at odds with the early characterization of MITF as a proliferative factor and its designation as a lineage survival oncogene (Widlund et al, 2002; Garraway et al, 2005). This paradox is explained by the rheostat model of MITF action (Carreira et al, 2006; reviewed in Goding and Arnheiter, 2019). In this model, cells with low overall levels of MITF activity exhibit a stem-cell-like phenotype, characterized by a low proliferation rate imposed by CDKN1B (p27kip1)-mediated cell cycle arrest, and high invasive potential by virtue of reorganization of the actin cytoskeleton and expression of matrix metalloproteases (Carreira et al, 2006). Cells with intermediate levels of MITF activity escape CDKN1B-imposed restraint on proliferation, while higher levels of MITF activity result in resumed cell-cycle arrest dependent on CDKN1A/p21 or the CDKN2A gene protein product p16 and a differentiation/pigmentation phenotype (Loercher et al, 2005; Carreira et al, 2005).
Literature References
PubMed ID Title Journal Year
17182868 Mitf regulation of Dia1 controls melanoma proliferation and invasiveness

Nuciforo, P, Carreira, S, Goodall, J, Rodriguez, M, Goding, CR, Denat, L, Larue, L, Testori, A, Hoek, KS

Genes Dev 2006
31123060 MITF-the first 25 years

Arnheiter, H, Goding, CR

Genes Dev 2019
12235125 Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor

Widlund, HR, Wu, M, Fisher, DE, Cui, J, Price, ER, Lessnick, SL, He, X, Horstmann, MA

J Cell Biol 2002
15623583 MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A

Loercher, AE, Harbour, JW, Delston, RB, Tank, EM

J Cell Biol 2005
15716956 Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression

Galibert, MD, Aksan, I, Carreira, S, Goodall, J, La Rocca, SA, Goding, CR, Denat, L, Larue, L

Nature 2005
16001072 Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma

Golub, TR, Fisher, DE, Ramaswamy, S, Garraway, LA, Li, C, Meyerson, ML, Widlund, HR, Beroukhim, R, Wagner, SN, Lee, C, Getz, G, Rimm, DL, Granter, SR, Berger, AJ, Milner, DA, Sellers, WR, Du, J, Rubin, MA

Nature 2005
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Authored
Rothfels, K  (2023-01-26)
Reviewed
de la Serna, IL  (2024-05-21)
Arnheiter, H  (2024-02-26)
Steingrímsson, E  (2024-11-05)
Vu, HN  (2024-11-05)
Created
Rothfels, K  (2023-01-27)
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