title: Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation.
abstract: 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.
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Shi Yun
authors.initials: SY
authors.lastname: Yeo
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Itahana
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Alvin Kunyao
authors.initials: AK
authors.lastname: Guo
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Rachel
authors.initials: R
authors.lastname: Han
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Kozue
authors.initials: K
authors.lastname: Iwamoto
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Hung Thanh
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Kai
authors.initials: K
authors.lastname: Kleiber
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, , Singapore.
authors.forename: Ya Jun
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, , Singapore.
authors.forename: Boon Huat
authors.initials: BH
authors.lastname: Bay
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Mathijs
authors.initials: M
authors.lastname: Voorhoeve
authors.affiliation: Cancer & Stem Cell Biology Program, Duke-NUS Medical School, , Singapore.
authors.forename: Koji
authors.identifier: http://orcid.org/0000-0002-7241-2894
authors.initials: K
authors.lastname: Itahana
mesh_terms: D000818:Animals; D001343:Autophagy; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000201:enzymology* / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005820:Genetic Testing; D064593:Heterografts; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C000717608:TGM2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: CDKN1A; TGM2; TP53; autophagy; chromosomes; genes; human; human biology; medicine; mouse; oncogenic transformation