p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.
p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.
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DOI：
10.1016/j.ccell.2019.01.006
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发表时间：
2019-02-11
期刊：
影响因子：
50.3
通讯作者：
Genovese G
中科院分区：
文献类型：
--
作者：
Carugo A;Minelli R;Sapio L;Soeung M;Carbone F;Robinson FS;Tepper J;Chen Z;Lovisa S;Svelto M;Amin S;Srinivasan S;Del Poggetto E;Loponte S;Puca F;Dey P;Malouf GG;Su X;Li L;Lopez-Terrada D;Rakheja D;Lazar AJ;Netto GJ;Rao P;Sgambato A;Maitra A;Tripathi DN;Walker CL;Karam JA;Heffernan TP;Viale A;Roberts CWM;Msaouel P;Tannir NM;Draetta GF;Genovese G
染色质重塑基因的改变越来越多地与人类肿瘤的发生有关。具体地说，SWI/SNF亚单位SMARCB1的双等位基因失活导致了极具侵袭性的儿科恶性肿瘤的出现。在这里，我们开发了恶性横纹肌样肿瘤(MRT)的胚胎马赛克小鼠模型，该模型忠实地概括了人类疾病的临床病理特征。我们证明SMARCB1基因缺陷的恶性肿瘤通过基因完整的MYC-p19ARF-P53轴表现出显著的未折叠蛋白反应(UPR)和内质网(ER)应激反应的激活。因此，这些肿瘤对诱导蛋白毒性应激和抑制自噬机制的药物表现出极高的敏感性。总之，我们的发现为药物重新定位试验提供了理论基础，这些试验调查针对SMARCB1缺陷的MRT中UPR和自噬的药物组合。通过建立SMARCB1缺陷的恶性横纹肌样肿瘤(MRT)的小鼠模型，Carugo等人。研究发现，SMARCB1的缺失通过MYC-p19ARF-P53轴激活未折叠的蛋白反应、内质网应激反应和自噬，在SMARB1缺陷的MRT中增加了对蛋白酶体和自噬抑制剂的敏感性。
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 (MRT) 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 endoplasmic reticulum (ER) stress response via 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 rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRT. By generating mouse models of SMARCB1-deficient malignant rhabdoid tumors (MRT), Carugo et al. find that loss of SMARCB1 activates the unfolded protein response, the ER stress response, and autophagy via a MYC–p19ARF–p53 axis, conferring sensitivity to proteasome and autophagy inhibitors in SMARB1-deficient MRT.
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影响因子：
16.6
作者：
Han ZY;Richer W;Fréneaux P;Chauvin C;Lucchesi C;Guillemot D;Grison C;Lequin D;Pierron G;Masliah-Planchon J;Nicolas A;Ranchère-Vince D;Varlet P;Puget S;Janoueix-Lerosey I;Ayrault O;Surdez D;Delattre O;Bourdeaut F
通讯作者：
Bourdeaut F
影响因子：
64.8
作者：
BUCKBINDER, L;TALBOTT, R;KLEY, N
通讯作者：
KLEY, N
影响因子：
13.5
作者：
Heo, Jeonghoon;Factor, Valentina M.;Thorgeirsson, Snorri S.
通讯作者：
Thorgeirsson, Snorri S.
影响因子：
46.9
作者：
Dantuma, NP;Lindsten, K;Masucci, MG
通讯作者：
Masucci, MG
影响因子：
50.3
作者：
Johann, Pascal D.;Erkek, Serap;Kool, Marcel
通讯作者：
Kool, Marcel