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Oncogene 2020 Mar 01;3913:2692-2706. doi: 10.1038/s41388-020-1173-z.
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RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis.

Naert T , Dimitrakopoulou D , Tulkens D , Demuynck S , Carron M , Noelanders R , Eeckhout L , Van Isterdael G , Deforce D , Vanhove C , Van Dorpe J , Creytens D , Vleminckx K .

Alterations of the retinoblastoma and/or the p53 signaling network are associated with specific cancers such as high-grade astrocytoma/glioblastoma, small-cell lung cancer (SCLC), choroid plexus tumors, and small-cell pancreatic neuroendocrine carcinoma (SC-PaNEC). However, the intricate functional redundancy between RB1 and the related pocket proteins RBL1/p107 and RBL2/p130 in suppressing tumorigenesis remains poorly understood. Here we performed lineage-restricted parallel inactivation of rb1 and rbl1 by multiplex CRISPR/Cas9 genome editing in the true diploid Xenopus tropicalis to gain insight into this in vivo redundancy. We show that while rb1 inactivation is sufficient to induce choroid plexus papilloma, combined rb1 and rbl1 inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimicking tp53 mutant X. tropicalis line, we demonstrate increased malignancy of rb1/rbl1-mutant glioma towards glioblastoma upon concomitant inactivation of tp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, the tp53 status had little effect on the establishment and growth of SC-PaNEC, but may rather be essential for maintaining chromosomal stability. SCLC was only rarely observed in our experimental setup, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1, generating new insights in the functional redundancy within the retinoblastoma protein family in suppressing neuroendocrine pancreatic cancer and glioma/glioblastoma.

PubMed ID: 32001819
Article link: Oncogene
Grant support: [+]

Genes referenced: cd3e cd3g ezh2 pcna pten rb1 rbl1 tp53
Antibodies: Cd3e Ab3 Ezh2 Ab3 GFAP Ab3 H3f3a Ab36 Mhc2a Ab1 Pcna Ab1
gRNAs referenced: pten gRNA2 rb1 gRNA1 rbl1 gRNA1 tp53 gRNA1 tp53 gRNA2

Disease Ontology terms: medulloblastoma [+]
Phenotypes: Xtr Wt + rb1 CRISPR + rbl1 CRISPR + tp53 CRISPR (Fig. 2 B) [+]

Article Images: [+] show captions
References [+] :
Abou-El-Ardat, Comprehensive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and heterogeneity of glioblastomas. 2017, Pubmed