The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

K. Evangelou; J. Bartkova; A. Kotsinas; I.S. Pateras; M. Liontos; G. Velimezi; M. Kosar; T. Liloglou; I.P. Trougakos; L. Dyrskjot; C.L. Andersen; M. Papaioannou; Y. Drosos; G. Papafotiou; Z. Hodny; B. Sosa-Pineda; X.-R. Wu; A. Klinakis; Torben Falck Ørntoft; J. Lukas; J. Bartek; V.G. Gorgoulis

doi:10.1038/cdd.2013.76

The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

K. Evangelou, J. Bartkova, A. Kotsinas, I.S. Pateras, M. Liontos, G. Velimezi, M. Kosar, T. Liloglou, I.P. Trougakos, L. Dyrskjot, C.L. Andersen, M. Papaioannou, Y. Drosos, G. Papafotiou, Z. Hodny, B. Sosa-Pineda, X.-R. Wu, A. Klinakis, Torben Falck Ørntoft, J. LukasJ. Bartek, V.G. Gorgoulis

Novo Nordisk Foundation Center for Protein Research

46 Citations (Scopus)

Abstract

Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16 ^INK4A, a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

Original language	English
Journal	Cell Death and Differentiation
Volume	20
Issue number	11
Pages (from-to)	1485-1497
Number of pages	13
ISSN	1350-9047
DOIs	https://doi.org/10.1038/cdd.2013.76
Publication status	Published - 1 Nov 2013

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Evangelou, K., Bartkova, J., Kotsinas, A., Pateras, I. S., Liontos, M., Velimezi, G., Kosar, M., Liloglou, T., Trougakos, I. P., Dyrskjot, L., Andersen, C. L., Papaioannou, M., Drosos, Y., Papafotiou, G., Hodny, Z., Sosa-Pineda, B., Wu, X.-R., Klinakis, A., Ørntoft, T. F., ... Gorgoulis, V. G. (2013). The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis. Cell Death and Differentiation, 20(11), 1485-1497. https://doi.org/10.1038/cdd.2013.76

Evangelou, K, Bartkova, J, Kotsinas, A, Pateras, IS, Liontos, M, Velimezi, G, Kosar, M, Liloglou, T, Trougakos, IP, Dyrskjot, L, Andersen, CL, Papaioannou, M, Drosos, Y, Papafotiou, G, Hodny, Z, Sosa-Pineda, B, Wu, X-R, Klinakis, A, Ørntoft, TF, Lukas, J, Bartek, J & Gorgoulis, VG 2013, 'The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis', Cell Death and Differentiation, vol. 20, no. 11, pp. 1485-1497. https://doi.org/10.1038/cdd.2013.76

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abstract = "Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16 INK4A, a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.",

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AU - Evangelou, K.

AU - Bartkova, J.

AU - Kotsinas, A.

AU - Pateras, I.S.

AU - Liontos, M.

AU - Velimezi, G.

AU - Kosar, M.

AU - Liloglou, T.

AU - Trougakos, I.P.

AU - Dyrskjot, L.

AU - Andersen, C.L.

AU - Papaioannou, M.

AU - Drosos, Y.

AU - Papafotiou, G.

AU - Hodny, Z.

AU - Sosa-Pineda, B.

AU - Wu, X.-R.

AU - Klinakis, A.

AU - Ørntoft, Torben Falck

AU - Lukas, J.

AU - Bartek, J.

AU - Gorgoulis, V.G.

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16 INK4A, a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

AB - Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16 INK4A, a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

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The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

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