Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression

Lidija Klampfer, Jie Huang, Georgia Corner, John Mariadason, Diego Arango, Takehiko Sasazuki, Senji Shirasawa, Leonard Augenlicht

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Endogenous interferon γ (IFNγ) promotes the host response to primary tumors, and IFNγ-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFNγ receptors did not differ among the isogenic cell lines. IFNγ stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFNγ.

Original languageEnglish
Pages (from-to)46278-46287
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number47
DOIs
Publication statusPublished - Nov 21 2003
Externally publishedYes

Fingerprint

Interferons
Genes
Tumors
Cells
Cell Line
Neoplasms
Colonic Neoplasms
Mutation
STAT2 Transcription Factor
Alleles
Interferon Receptors
STAT1 Transcription Factor
Tumor Escape
HCT116 Cells
HEK293 Cells
Transcription
Reporter Genes
Clone Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Klampfer, L., Huang, J., Corner, G., Mariadason, J., Arango, D., Sasazuki, T., ... Augenlicht, L. (2003). Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression. Journal of Biological Chemistry, 278(47), 46278-46287. https://doi.org/10.1074/jbc.M304721200

Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression. / Klampfer, Lidija; Huang, Jie; Corner, Georgia; Mariadason, John; Arango, Diego; Sasazuki, Takehiko; Shirasawa, Senji; Augenlicht, Leonard.

In: Journal of Biological Chemistry, Vol. 278, No. 47, 21.11.2003, p. 46278-46287.

Research output: Contribution to journalArticle

Klampfer, L, Huang, J, Corner, G, Mariadason, J, Arango, D, Sasazuki, T, Shirasawa, S & Augenlicht, L 2003, 'Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression', Journal of Biological Chemistry, vol. 278, no. 47, pp. 46278-46287. https://doi.org/10.1074/jbc.M304721200
Klampfer, Lidija ; Huang, Jie ; Corner, Georgia ; Mariadason, John ; Arango, Diego ; Sasazuki, Takehiko ; Shirasawa, Senji ; Augenlicht, Leonard. / Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 47. pp. 46278-46287.
@article{4b62d014e5454387a914c46f9bd0456b,
title = "Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression",
abstract = "Endogenous interferon γ (IFNγ) promotes the host response to primary tumors, and IFNγ-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFNγ receptors did not differ among the isogenic cell lines. IFNγ stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFNγ.",
author = "Lidija Klampfer and Jie Huang and Georgia Corner and John Mariadason and Diego Arango and Takehiko Sasazuki and Senji Shirasawa and Leonard Augenlicht",
year = "2003",
month = "11",
day = "21",
doi = "10.1074/jbc.M304721200",
language = "English",
volume = "278",
pages = "46278--46287",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "47",

}

TY - JOUR

T1 - Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression

AU - Klampfer, Lidija

AU - Huang, Jie

AU - Corner, Georgia

AU - Mariadason, John

AU - Arango, Diego

AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

AU - Augenlicht, Leonard

PY - 2003/11/21

Y1 - 2003/11/21

N2 - Endogenous interferon γ (IFNγ) promotes the host response to primary tumors, and IFNγ-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFNγ receptors did not differ among the isogenic cell lines. IFNγ stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFNγ.

AB - Endogenous interferon γ (IFNγ) promotes the host response to primary tumors, and IFNγ-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFNγ receptors did not differ among the isogenic cell lines. IFNγ stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFNγ.

UR - http://www.scopus.com/inward/record.url?scp=0345306729&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0345306729&partnerID=8YFLogxK

U2 - 10.1074/jbc.M304721200

DO - 10.1074/jbc.M304721200

M3 - Article

VL - 278

SP - 46278

EP - 46287

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 47

ER -