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
  • [21] N-RAS and K-RAS genes mutations in Brazilian patients with multiple myeloma
    Lima, Carmen S.
    Ortega, Manoela M.
    Faria, Rosa M.
    Shitara, Edson S.
    Assis, Angela M.
    Albuquerque, Dulcineia M.
    Oliveira, Jose S.
    Noguti, Maria A.
    Faria, Jose R.
    Costa, Fernando F.
    ANNALS OF ONCOLOGY, 2006, 17 : 206 - 206
  • [22] Comparison of K-Ras and N-Ras Mutagenic Hot Spots for UVC Damage
    Nair, Sindhu G.
    Loppnow, Glen R.
    ACS OMEGA, 2019, 4 (02): : 3469 - 3475
  • [23] N-RAS and K-RAS gene mutations in Brazilian patients with multiple myeloma
    Ortega, MM
    Faria, RMD
    Shitara, ES
    Assis, AM
    Albuquerque, DM
    Oliveira, JSR
    Noguti, MAE
    Faria, JR
    Costa, FF
    Lima, CSP
    LEUKEMIA & LYMPHOMA, 2006, 47 (02) : 285 - 289
  • [24] K-ras is an essential gene in the mouse with partial functional overlap with N-ras
    Johnson, L
    Greenbaum, D
    Cichowski, K
    Mercer, K
    Murphy, E
    Schmitt, E
    Bronson, RT
    Umanoff, H
    Edelmann, W
    Kucherlapati, R
    Jacks, T
    GENES & DEVELOPMENT, 1997, 11 (19) : 2468 - 2481
  • [25] Clinical relevance of H-RAS, K-RAS, and N-RAS mRNA expression in primary breast cancer patients
    Malgorzata Banys-Paluchowski
    Karin Milde-Langosch
    Tanja Fehm
    Isabell Witzel
    Leticia Oliveira-Ferrer
    Barbara Schmalfeldt
    Volkmar Müller
    Breast Cancer Research and Treatment, 2020, 179 : 403 - 414
  • [26] Brother's Keeper: Wild-Type Mutant K-Ras Dimers Limit Oncogenesis
    Lin, Yi-Jang
    Haigis, Kevin M.
    CELL, 2018, 172 (04) : 645 - 647
  • [27] Clinical relevance of H-RAS, K-RAS, and N-RAS mRNA expression in primary breast cancer patients
    Banys-Paluchowski, Malgorzata
    Milde-Langosch, Karin
    Fehm, Tanja
    Witzel, Isabell
    Oliveira-Ferrer, Leticia
    Schmalfeldt, Barbara
    Mueller, Volkmar
    BREAST CANCER RESEARCH AND TREATMENT, 2020, 179 (02) : 403 - 414
  • [28] The role of CCN1 in mutant K-RAS addiction in pancreatic cancer
    Kambhampati, Anjali
    De, Archana
    Haque, Inamul
    Banerjee, Snigdha
    Banerjee, Sushanta K.
    CANCER RESEARCH, 2024, 84 (06)
  • [29] The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics
    Romano, David
    Maccario, Helene
    Doherty, Carolanne
    Quinn, Niall P.
    Kolch, Walter
    Matallanas, David
    MOLECULAR AND CELLULAR BIOLOGY, 2013, 33 (09) : 1859 - 1868
  • [30] INFREQUENT INVOLVEMENT OF MUTATIONS ON NEUROFIBROMATOSIS TYPE-1, H-RAS, K-RAS AND N-RAS IN UROTHELIAL TUMORS
    UCHIDA, T
    WADA, C
    ISHIDA, H
    EGAWA, S
    AO, T
    YOKOYAMA, E
    KOSHIBA, K
    UROLOGIA INTERNATIONALIS, 1995, 55 (02) : 63 - 67