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Autophagic activity dictates the cellular response to oncogenic RAS

Autophagic activity dictates the cellular response to oncogenic RAS
Autophagic activity dictates the cellular response to oncogenic RAS
RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2(?3/?3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.
0027-8424
13325-13330
Wang, Y.
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Wang, X.D.
193a8d85-f6a6-4501-be84-a756cdd3c24b
Lapi, E.
45a6e61a-5b70-4fd2-87f3-4db11f90bbaf
Sullivan, A.
0ca86d30-e1b1-4f41-b185-ba95ac2194ce
Jia, W.
3b3668a0-3383-41f6-b86c-8b2b1ec2214d
He, Y.-W.
b140e3e0-31bd-4755-8abf-67739bdf8d5a
Ratnayaka, I.
9c47107b-88d9-4c7e-8172-f468d45a2b00
Zhong, S.
e52648be-29fe-4597-bece-e28eec163b8b
Goldin, R.D.
61032798-41c5-4047-8a69-f0cc05c853d5
Goemans, C.G.
5798d136-4239-43d4-84b2-007bd11f5a21
Tolkovsky, A.M.
8390d11a-729b-47d8-a2be-76c44edfc8e6
Lu, X.
8a249ba9-6273-4b53-8cf8-ffcd51be627a
Wang, Y.
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Wang, X.D.
193a8d85-f6a6-4501-be84-a756cdd3c24b
Lapi, E.
45a6e61a-5b70-4fd2-87f3-4db11f90bbaf
Sullivan, A.
0ca86d30-e1b1-4f41-b185-ba95ac2194ce
Jia, W.
3b3668a0-3383-41f6-b86c-8b2b1ec2214d
He, Y.-W.
b140e3e0-31bd-4755-8abf-67739bdf8d5a
Ratnayaka, I.
9c47107b-88d9-4c7e-8172-f468d45a2b00
Zhong, S.
e52648be-29fe-4597-bece-e28eec163b8b
Goldin, R.D.
61032798-41c5-4047-8a69-f0cc05c853d5
Goemans, C.G.
5798d136-4239-43d4-84b2-007bd11f5a21
Tolkovsky, A.M.
8390d11a-729b-47d8-a2be-76c44edfc8e6
Lu, X.
8a249ba9-6273-4b53-8cf8-ffcd51be627a

Wang, Y., Wang, X.D., Lapi, E., Sullivan, A., Jia, W., He, Y.-W., Ratnayaka, I., Zhong, S., Goldin, R.D., Goemans, C.G., Tolkovsky, A.M. and Lu, X. (2012) Autophagic activity dictates the cellular response to oncogenic RAS. Proceedings of the National Academy of Sciences, 109 (33), 13325-13330. (doi:10.1073/pnas.1120193109).

Record type: Article

Abstract

RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2(?3/?3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.

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More information

Accepted/In Press date: 10 July 2012
Published date: 14 August 2012
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 385902
URI: http://eprints.soton.ac.uk/id/eprint/385902
ISSN: 0027-8424
PURE UUID: d1e227bc-960a-4c1f-b053-baa8ed407b11
ORCID for Y. Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 26 Jan 2016 09:43
Last modified: 15 Mar 2024 03:52

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Contributors

Author: Y. Wang ORCID iD
Author: X.D. Wang
Author: E. Lapi
Author: A. Sullivan
Author: W. Jia
Author: Y.-W. He
Author: I. Ratnayaka
Author: S. Zhong
Author: R.D. Goldin
Author: C.G. Goemans
Author: A.M. Tolkovsky
Author: X. Lu

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