Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation

被引:2
|
作者
Ferguson, Robert [1 ]
Aughton, Karen [1 ]
Evans, Anthony [1 ]
Shaw, Victoria [1 ]
Armstrong, Jane [1 ]
Ware, Adam [1 ]
Bennett, Laura [1 ]
Costello, Eithne [1 ]
Greenhalf, William [1 ]
机构
[1] Univ Liverpool, Liverpool Expt Canc Med Ctr, Liverpool L3 5TR, England
关键词
pancreatic ductal adenocarcinoma; K-Ras; N-Ras; G2; cyclins; DUCTAL ADENOCARCINORNA; EGF RECEPTOR; KRAS; MUTATIONS; GENE; ADDICTION; EMT; D1;
D O I
10.3390/cimb45030164
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited.
引用
收藏
页码:2505 / 2520
页数:16
相关论文
共 50 条
  • [41] Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation
    Nussinov, Ruth
    Tsai, Chung-Jung
    Muratcioglu, Serena
    Jang, Hyunbum
    Gursoy, Attila
    Keskin, Ozlem
    EXPERT REVIEW OF PROTEOMICS, 2015, 12 (06) : 669 - 682
  • [42] Activated mutant K-ras and K-ras nullizygosity reduce differentiation in murine embryonic stem cell tumours
    James, RM
    Plowman, S
    Miles, C
    West, JD
    Brooks, DG
    Patek, CE
    Arends, MJ
    JOURNAL OF PATHOLOGY, 2003, 201 : 5A - 5A
  • [43] Pancreatic cancer cell radiation survival and prenyltransferase inhibition: The role of K-ras
    Brunner, TB
    Cengel, KA
    Hahn, SM
    Wu, HM
    Fraker, DL
    McKenna, WG
    Bernhard, EJ
    CANCER RESEARCH, 2005, 65 (18) : 8433 - 8441
  • [44] Identification of Mutant K-Ras-dependent Phenotypes Using a Panel of Isogenic Cell Lines
    Vartanian, Steffan
    Bentley, Carolyn
    Brauer, Matthew J.
    Li, Li
    Shirasawa, Senji
    Sasazuki, Takehiko
    Kim, Jung-Sik
    Haverty, Pete
    Stawiski, Eric
    Modrusan, Zora
    Waldman, Todd
    Stokoe, David
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (04) : 2403 - 2413
  • [45] Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon
    Haigis, Kevin M.
    Kendall, Krystle R.
    Wang, Yufang
    Cheung, Ann
    Haigis, Marcia C.
    Glickman, Jonathan N.
    Niwa-Kawakita, Michiko
    Sweet-Cordero, Alejandro
    Sebolt-Leopold, Judith
    Shannon, Kevin M.
    Settleman, Jeffrey
    Giovannini, Marco
    Jacks, Tyler
    NATURE GENETICS, 2008, 40 (05) : 600 - 608
  • [46] Transcriptional activation of H-ras, K-ras and N-ras proto-oncogenes in human bladder tumors
    Vageli, D
    Kiaris, H
    Delakas, D
    Anezinis, P
    Cranidis, A
    Spandidos, DA
    CANCER LETTERS, 1996, 107 (02) : 241 - 247
  • [47] Prognostic significance of N-RAS and K-RAS mutations in 232 patients with acute myelold leukemia
    Ritter, M
    Kim, TD
    Lisske, K
    Thiede, C
    Schaich, T
    Neubauer, A
    HAEMATOLOGICA, 2004, 89 (11) : 1397 - 1399
  • [48] K-Ras mutations and N-Ras mutations in childhood acute leukemias with and without MLL rearrangements
    Liang, DC
    Shih, LY
    Lai, CL
    Lin, TH
    Fu, JF
    Li, HY
    Wang, HI
    Hung, LJ
    Yang, CP
    Jaing, TH
    Chen, SH
    Liu, HC
    Wang, LY
    BLOOD, 2005, 106 (11) : 799A - 799A
  • [49] The K-Ras, N-Ras, and H-Ras Isoforms: Unique Conformational Preferences and Implications for Targeting Oncogenic Mutants
    Parker, Jillian A.
    Mattos, Carla
    COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 2018, 8 (08):
  • [50] Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon
    Kevin M Haigis
    Krystle R Kendall
    Yufang Wang
    Ann Cheung
    Marcia C Haigis
    Jonathan N Glickman
    Michiko Niwa-Kawakita
    Alejandro Sweet-Cordero
    Judith Sebolt-Leopold
    Kevin M Shannon
    Jeffrey Settleman
    Marco Giovannini
    Tyler Jacks
    Nature Genetics, 2008, 40 : 600 - 608