MITF-M-dependent expression of CDKN2A gene product 16INK4A

Stable Identifier
R-HSA-9858651
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
nucleoplasm, cytosol
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
MITF-M-dependent expression of CDKN2A gene product 16INK4A
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
CDKN2A encodes the cyclin-dependent kinase inhibitor p16INK4A, which promotes cell cycle arrest by binding to cyclin-dependent kinases CDK4 and CDK6 and preventing interaction with D-type cyclins (CCNDs). In melanocytes, p16INK4A expression is regulated in part by the binding of MITF to M- and E-box elements in its promoter. MITF-dependent p16INK4A expression results in cell cycle arrest accompanied by an increase in hypophosphorylated RB1 and a change in morphology consistent with differentiation (Loercher et al, 2005). This is consistent with earlier work showing that melanocytes from mice lacking p16 INK4A had higher proliferation rates and were less differentiated than melanocytes with one or both copies of p16 INK4A intact (Sviderskaya et al, 2002). In addition, germline loss-of-function mutations of p16INK4A are associated with familial melanoma syndrome (Hussussian et al, 1994) (
According to the rheostat model of MITF-dependent gene regulation, p16INK4A contributes to differentiation and cell cycle arrest at high levels of MITF activity (reviewed in Hoek and Goding, 2010; Cheli et al, 2010; Hartman and Czyz, 2015, Goding and Arnheiter, 2019).
Literature References
PubMed ID Title Journal Year
11904317 p16(Ink4a) in melanocyte senescence and differentiation

Sviderskaya, EV, Hill, SP, Evans-Whipp, TJ, Chin, L, Orlow, SJ, Easty, DJ, Cheong, SC, Beach, D, DePinho, RA, Bennett, DC

J Natl Cancer Inst 2002
25142731 Pro-survival role of MITF in melanoma

Hartman, ML, Czyz, M

J Invest Dermatol 2015
19995375 Fifteen-year quest for microphthalmia-associated transcription factor target genes

Cheli, Y, Ohanna, M, Ballotti, R, Bertolotto, C

Pigment Cell Melanoma Res 2010
31123060 MITF-the first 25 years

Goding, CR, Arnheiter, H

Genes Dev 2019
20726948 Cancer stem cells versus phenotype-switching in melanoma

Hoek, KS, Goding, CR

Pigment Cell Melanoma Res 2010
15623583 MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A

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

J Cell Biol 2005
7987387 Germline p16 mutations in familial melanoma

Hussussian, CJ, Struewing, JP, Goldstein, AM, Higgins, PA, Ally, DS, Sheahan, MD, Clark, WH, Tucker, MA, Dracopoli, NC

Nat Genet 1994
Participants
Input
Output
Participates
as an event of
This event is regulated
Positively by
Regulator
MITF-M dimer:CDKN2A gene [nucleoplasm] (Homo sapiens)
Active Unit
MITF-M dimer [nucleoplasm]
Authored
Rothfels, K  (2023-12-21)
Reviewed
Arnheiter, H  (2024-02-26)
de la Serna, IL  (2024-05-21)
Vu, HN  (2024-11-05)
Steingrímsson, E  (2024-11-05)
Created
Rothfels, K  (2024-01-13)
Cite Us!