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P53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.


ABSTRACT: Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

SUBMITTER: Carugo A 

PROVIDER: S-EPMC7876656 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.

Carugo Alessandro A   Minelli Rosalba R   Sapio Luigi L   Soeung Melinda M   Carbone Federica F   Robinson Frederick S FS   Tepper James J   Chen Ziheng Z   Lovisa Sara S   Svelto Maria M   Amin Samirkumar S   Srinivasan Sanjana S   Del Poggetto Edoardo E   Loponte Sara S   Puca Francesca F   Dey Prasenjit P   Malouf Gabriel G GG   Su Xiaoping X   Li Liren L   Lopez-Terrada Dolores D   Rakheja Dinesh D   Lazar Alexander J AJ   Netto George J GJ   Rao Priya P   Sgambato Alessandro A   Maitra Anirban A   Tripathi Durga N DN   Walker Cheryl L CL   Karam Jose A JA   Heffernan Timothy P TP   Viale Andrea A   Roberts Charles W M CWM   Msaouel Pavlos P   Tannir Nizar M NM   Draetta Giulio F GF   Genovese Giannicola G  

Cancer cell 20190201 2


Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the  ...[more]

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