Selective Role for Mek1 but not Mek2 in the Induction of Epidermal Neoplasia

被引:43
|
作者
Scholl, Florence A. [1 ,2 ]
Dumesic, Phillip A. [1 ,2 ]
Barragan, Deborah I. [1 ,2 ]
Harada, Kazutoshi [3 ]
Charron, Jean [4 ]
Khavari, Paul A. [1 ,2 ]
机构
[1] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA
[2] Vet Affairs Palo Alto Healthcare Syst, Palo Alto, CA USA
[3] Univ Yamanashi, Fac Med, Dept Dermatol, Chuo Ku, Yamanashi, Japan
[4] Univ Laval, Ctr Rech Cancerol, CHUQ, Hotel Dieu, Quebec City, PQ, Canada
关键词
RAS; ACTIVATION; MUTATION; KINASE; GROWTH;
D O I
10.1158/0008-5472.CAN-08-1963
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The Ras/Raf/Mck/Erk mitogen-activated protein kinase pathway regulates fundamental processes in normal and malignant cells, including proliferation, differentiation, and cell survival. Mutations in this pathway have been associated with carcinogenesis and developmental disorders, making Mek1 and Mek2 prime therapeutic targets. In this study, we examined the requirement for Mek1 and Mek2 in skin neoplasia using the two-step 7,12-dimethylbenz(a)anthraacene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) skin carcinogenesis model. Mice lacking epidermal Mek1 protein develop fewer papillomas than both wild-type and Mek2-null mice following DMBA/TPA treatment. Mek1 knockout mice had smaller papillomas, delayed tumor onset, and half the tumor burden of wild-type mice. Loss of one Mek1 allele, however, did not affect tumor development, indicating that one Mek1 allele is sufficient for normal papilloma formation. No difference in TPA-induced hyperproliferation, inflammation, or Erk activation was observed between wildtype, conditional Mek1 knockout, and Mek2-null mice, indicating that Mek1 findings were not due to a general failure of these processes. These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting. [Cancer Res 2009;69(9):3772-8]
引用
收藏
页码:3772 / 3778
页数:7
相关论文
共 50 条
  • [1] Mek1, but not Mek2, alters epidermal growth and differentiation
    Scholl, FA
    Dumesic, PA
    Charron, J
    Khavari, P
    JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2004, 122 (03) : A77 - A77
  • [2] Putative allosteric MEK1 and MEK2 inhibitors
    Price, Steve
    EXPERT OPINION ON THERAPEUTIC PATENTS, 2008, 18 (06) : 603 - 627
  • [3] Mek1 and Mek2 Functional Redundancy in Erythropoiesis
    Beuret, Laurent
    Fortier-Beaulieu, Simon-Pierre
    Rondeau, Vincent
    Roy, Sophie
    Houde, Nicolas
    Balabanian, Karl
    Espeli, Marion
    Charron, Jean
    FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2021, 9
  • [4] Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect
    Aoidi, Rifdat
    Maltais, Annie
    Charron, Jean
    SCIENCE SIGNALING, 2016, 9 (412)
  • [5] Differential expression of MEK1 and MEK2 during mouse development
    Alessandrini, A
    Brott, BK
    Erikson, RL
    CELL GROWTH & DIFFERENTIATION, 1997, 8 (05): : 505 - 511
  • [6] Mek1 and Mek2 functions in the formation of the blood placental barrier
    Nadeau, Valerie
    Bissonauth, Vickram
    Charron, Jean
    M S-MEDECINE SCIENCES, 2012, 28 (04): : 409 - 415
  • [7] Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells
    Wu, XY
    Noh, SJ
    Zhou, GC
    Dixon, JE
    Guan, KL
    JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (06) : 3265 - 3271
  • [8] Characterization and functional analysis of grouper (Epinephelus coioides) MEK1 and MEK2
    Mo, Ze-Quan
    Han, Rui
    Wang, Jiu-Le
    Ni, Lu-Yun
    Su, Yu-Ling
    Lai, Xue-Li
    He, Zhi-Chang
    Chen, Hong-Ping
    Li, Yan-Wei
    Sun, Hong-Yan
    Luo, Xiao-Chun
    Dan, Xue-Ming
    FISH & SHELLFISH IMMUNOLOGY, 2019, 84 : 1090 - 1097
  • [9] Involvement of MEK1 and MEK2 kinases in the maturation of the mouse immune system
    Houde, Nicolas
    Espeli, Marion
    Charron, Jean
    M S-MEDECINE SCIENCES, 2022, 38 (6-7): : 529 - 532
  • [10] MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
    Caunt, Christopher J.
    Sale, Matthew J.
    Smith, Paul D.
    Cook, Simon J.
    NATURE REVIEWS CANCER, 2015, 15 (10) : 577 - 592