Suppression of Ras-stimulated Transformation by the JNK Signal Transduction Pathway

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2003 Mar 12

PMID 12629045

Citations 58

Authors

Norman J Kennedy

Hayla K Sluss

Stephen N Jones

Dafna Bar-Sagi

Richard A Flavell

Roger J Davis

Affiliations

Soon will be listed here.

Abstract

The c-Jun NH(2)-terminal kinase (JNK) phosphorylates and activates members of the activator protein-1 (AP-1) group of transcription factors and is implicated in oncogenic transformation. To examine the role of JNK, we investigated the effect of JNK deficiency on Ras-stimulated transformation. We demonstrate that although JNK does play a role in transformation in vitro, JNK is not required for tumor development in vivo. Importantly, the loss of JNK expression resulted in substantial increases in the number and growth of tumor nodules in vivo. Complementation assays demonstrated that this phenotype was caused by JNK deficiency. These data demonstrate that, in contrast to expectations, the normal function of JNK may be to suppress tumor development in vivo. This conclusion is consistent with the presence in human tumors of loss-of-function mutations in the JNK pathway.

Citing Articles

Biphasic JNK-Erk signaling separates the induction and maintenance of cell senescence after DNA damage induced by topoisomerase II inhibition.

Netterfield T, Ostheimer G, Tentner A, Joughin B, Dakoyannis A, Sharma C Cell Syst. 2023; 14(7):582-604.e10.

PMID: 37473730 PMC: 10627503. DOI: 10.1016/j.cels.2023.06.005.

Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells.

Salem M, Gerges M, Noser A Sci Rep. 2022; 12(1):22146.

PMID: 36550279 PMC: 9780203. DOI: 10.1038/s41598-022-26571-7.

Potential effects of commonly applied drugs on neural stem cell proliferation and viability: A hypothesis-generating systematic review and meta-analysis.

Mortimer K, Vernon-Browne H, Zille M, Didwischus N, Boltze J Front Mol Neurosci. 2022; 15:975697.

PMID: 36277493 PMC: 9581168. DOI: 10.3389/fnmol.2022.975697.

Wnt7a inhibits transformed cell proliferation while promoting migration and invasion in non-small cell lung cancer.

Xu X, Xu S, Wei Z, Li J Transl Cancer Res. 2022; 9(8):4666-4675.

PMID: 35117830 PMC: 8797291. DOI: 10.21037/tcr-20-215.

Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy.

Jazirehi A Int J Mol Sci. 2021; 22(21).

PMID: 34769156 PMC: 8584081. DOI: 10.3390/ijms222111726.

References

Yoshida B, Dubauskas Z, Chekmareva M, Christiano T, Stadler W, Rinker-Schaeffer C . Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. 1999; 59(21):5483-7. View

Potapova O, Haghighi A, Bost F, Liu C, Birrer M, Gjerset R . The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. J Biol Chem. 1997; 272(22):14041-4. DOI: 10.1074/jbc.272.22.14041. View

Datta S, Brunet A, Greenberg M . Cellular survival: a play in three Akts. Genes Dev. 1999; 13(22):2905-27. DOI: 10.1101/gad.13.22.2905. View

Tournier C, Hess P, Yang D, Xu J, Turner T, Nimnual A . Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science. 2000; 288(5467):870-4. DOI: 10.1126/science.288.5467.870. View

Behrens A, Jochum W, Sibilia M, Wagner E . Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. Oncogene. 2000; 19(22):2657-63. DOI: 10.1038/sj.onc.1203603. View

Wu C, Li A, Chi C, Huang C, Shen K, Liu W . Human gastric cancer kinase profile and prognostic significance of MKK4 kinase. Am J Pathol. 2000; 156(6):2007-15. PMC: 1850082. DOI: 10.1016/s0002-9440(10)65073-0. View

Potapova O, Gorospe M, Bost F, Dean N, Gaarde W, Mercola D . c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells. J Biol Chem. 2000; 275(32):24767-75. DOI: 10.1074/jbc.M904591199. View

Sherr C, DePinho R . Cellular senescence: mitotic clock or culture shock?. Cell. 2000; 102(4):407-10. DOI: 10.1016/s0092-8674(00)00046-5. View

Davis R . Signal transduction by the JNK group of MAP kinases. Cell. 2000; 103(2):239-52. DOI: 10.1016/s0092-8674(00)00116-1. View

10.

Vogelstein B, Lane D, Levine A . Surfing the p53 network. Nature. 2000; 408(6810):307-10. DOI: 10.1038/35042675. View

11.

Soengas M, Capodieci P, Polsky D, Mora J, Esteller M, McCombie R . Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature. 2001; 409(6817):207-11. DOI: 10.1038/35051606. View

12.

Kim H, Vander Griend D, Yang X, Benson D, Dubauskas Z, Yoshida B . Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res. 2001; 61(7):2833-7. View

13.

Yoshida S, Fukino K, Harada H, Nagai H, Imoto I, Inazawa J . The c-Jun NH2-terminal kinase3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. J Hum Genet. 2001; 46(4):182-7. DOI: 10.1007/s100380170086. View

14.

Evan G, Vousden K . Proliferation, cell cycle and apoptosis in cancer. Nature. 2001; 411(6835):342-8. DOI: 10.1038/35077213. View

15.

Tournier C, Dong C, Turner T, Jones S, Flavell R, Davis R . MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 2001; 15(11):1419-26. PMC: 312702. DOI: 10.1101/gad.888501. View

16.

Zong W, LINDSTEN T, Ross A, Macgregor G, Thompson C . BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 2001; 15(12):1481-6. PMC: 312722. DOI: 10.1101/gad.897601. View

17.

Yu J, Zhang L, Hwang P, Kinzler K, Vogelstein B . PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell. 2001; 7(3):673-82. DOI: 10.1016/s1097-2765(01)00213-1. View

18.

Nakano K, Vousden K . PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001; 7(3):683-94. DOI: 10.1016/s1097-2765(01)00214-3. View

19.

Bennett B, Sasaki D, Murray B, OLeary E, Sakata S, Xu W . SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A. 2001; 98(24):13681-6. PMC: 61101. DOI: 10.1073/pnas.251194298. View

20.

Su G, Song J, Repasky E, Schutte M, Kern S . Mutation rate of MAP2K4/MKK4 in breast carcinoma. Hum Mutat. 2001; 19(1):81. DOI: 10.1002/humu.9002. View