Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation
Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mamma...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/07101 |
| _version_ | 1811180422564937728 |
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| author | Shi Yun Yeo Yoko Itahana Alvin Kunyao Guo Rachel Han Kozue Iwamoto Hung Thanh Nguyen Yi Bao Kai Kleiber Ya Jun Wu Boon Huat Bay Mathijs Voorhoeve Koji Itahana |
| author_facet | Shi Yun Yeo Yoko Itahana Alvin Kunyao Guo Rachel Han Kozue Iwamoto Hung Thanh Nguyen Yi Bao Kai Kleiber Ya Jun Wu Boon Huat Bay Mathijs Voorhoeve Koji Itahana |
| author_sort | Shi Yun Yeo |
| collection | DOAJ |
| description | Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation. |
| first_indexed | 2024-04-11T09:02:52Z |
| format | Article |
| id | doaj.art-81cca80787a441dfb2b58c6e42a290ba |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:02:52Z |
| publishDate | 2016-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-81cca80787a441dfb2b58c6e42a290ba2022-12-22T04:32:43ZengeLife Sciences Publications LtdeLife2050-084X2016-03-01510.7554/eLife.07101Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformationShi Yun Yeo0Yoko Itahana1Alvin Kunyao Guo2Rachel Han3Kozue Iwamoto4Hung Thanh Nguyen5Yi Bao6Kai Kleiber7Ya Jun Wu8Boon Huat Bay9Mathijs Voorhoeve10Koji Itahana11https://orcid.org/0000-0002-7241-2894Cancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeDepartment of Anatomy, Yong Loo Lin School of Medicine, National University Health System, SingaporeDepartment of Anatomy, Yong Loo Lin School of Medicine, National University Health System, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeCancer & Stem Cell Biology Program, Duke-NUS Medical School, SingaporeGenetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.https://elifesciences.org/articles/07101TGM2oncogenic transformationTP53autophagyCDKN1A |
| spellingShingle | Shi Yun Yeo Yoko Itahana Alvin Kunyao Guo Rachel Han Kozue Iwamoto Hung Thanh Nguyen Yi Bao Kai Kleiber Ya Jun Wu Boon Huat Bay Mathijs Voorhoeve Koji Itahana Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation eLife TGM2 oncogenic transformation TP53 autophagy CDKN1A |
| title | Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation |
| title_full | Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation |
| title_fullStr | Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation |
| title_full_unstemmed | Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation |
| title_short | Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation |
| title_sort | transglutaminase 2 contributes to a tp53 induced autophagy program to prevent oncogenic transformation |
| topic | TGM2 oncogenic transformation TP53 autophagy CDKN1A |
| url | https://elifesciences.org/articles/07101 |
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