MITF-M dimer binds the CDK2 gene

Stable Identifier
R-HSA-9858560
Type
Reaction [binding]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
MITF-M dimer binds the CDK2 gene
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
The gene for CDK2 is arranged in a head-to-head fashion with another MITF target gene PMEL (also known as SILV), and the intergenic region contains E-box elements that have been shown to be bound by MITF in vitro and in vivo to promote expression of both genes (Adachi and Lieber, 2002; Du et al, 2002; Du et al, 2004). ChIP studies in human melanoma cell lines show that MITF is bound to the promoter of the CDK2 gene (Du et al, 2003). Consistent with this, expression of a dominant-negative MITF in human primary melanocytes and a panel of melanoma cell lines abrogates CDK2 mRNA and protein levels (Du et a1, 2004). E-box element 2 was shown to be essential for MITF-M-dependent CDK2 expression, as mutation of this site abolishes expression of a CDK2 reporter gene and disrupts colony formation in melanoma cell lines (Du et al, 2004). MITF-dependent activation of CDK2 appears to be specific to the melanocyte lineage, as transfection of MITF into HEK293 cells, the colon cancer cell line SW480 or the breast cancer cell line T47D did not promote CDK2 reporter gene expression (Du et al, 2004). MITF-dependent CDK2 upregulation contributes to proliferative capacity of melanocytes and melanoma cells and to the development of HSP90 inhibitor resistance in melanoma (Du et al, 2004; Azimi et al, 2018; reviewed in Goding and Arnheiter, 2019).
Literature References
PubMed ID Title Journal Year
29507054 Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors

Hansson, J, Peeper, DS, Nielsen, J, Seashore-Ludlow, B, Tuominen, R, Caramuta, S, Altun, M, Azimi, A, Maddalo, G, Edfors, F, Boström, J, Uhlén, M, Robinson, JL, Kemper, K, Krijgsman, O, Egyhazi Brage, S

Mol Syst Biol 2018
31123060 MITF-the first 25 years

Arnheiter, H, Goding, CR

Genes Dev 2019
15607961 Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF

Golub, TR, Widlund, HR, Nishimura, EK, Fisher, DE, Ramaswamy, S, Ross, K, Huber, WE, Horstmann, MA, Du, J

Cancer Cell 2004
12110178 Bidirectional gene organization: a common architectural feature of the human genome

Lieber, MR, Adachi, N

Cell 2002
12819038 MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma

Widlund, HR, Fisher, DE, Ramaswamy, S, Horstmann, MA, Miller, AJ, Du, J

Am J Pathol 2003
Participants
Input
Output
Participates
as an event of
Authored
Rothfels, K  (2023-12-21)
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  (2024-01-13)
Cite Us!