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

Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S. Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G. Malouf, Xiaoping Su, Liren Li, Dolores Lopez-TerradaDinesh Rakheja, Alexander J. Lazar, George J. Netto, Priya Rao, Alessandro Sgambato, Anirban Maitra, Durga N. Tripathi, Cheryl L. Walker, Jose A. Karam, Timothy P. Heffernan, Andrea Viale, Charles W.M. Roberts, Pavlos Msaouel, Nizar M. Tannir, Giulio F. Draetta, Giannicola Genovese

Risultato della ricerca: Contributo in rivistaArticolo in rivista

20 Citazioni (Scopus)


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-p19 ARF -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.
Lingua originaleEnglish
pagine (da-a)204-220.e9
RivistaCancer Cell
Stato di pubblicazionePubblicato - 2019


  • Animals
  • Antineoplastic Agents
  • Autophagy
  • BIRC5
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • ER stress
  • Endoplasmic Reticulum Stress
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MYC
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteasome Inhibitors
  • Proteostasis
  • Proto-Oncogene Proteins c-myc
  • Rhabdoid Tumor
  • SMARCB1 Protein
  • Signal Transduction
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53
  • Unfolded Protein Response
  • autophagy
  • embryonic mosaic GEM models
  • p53
  • proteasome inhibitors
  • renal medullary carcinoma
  • rhabdoid tumors


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