SKP2 activation by thyroid hormone receptor β2 bypasses Rb-dependent proliferation in Rb-deficient cells Journal Article

Authors: Xu, X. L.; Li, Z.; Liu, A.; Fan, X.; Hu, D. N.; Qi, D. L.; Chitty, D. W.; Jia, R.; Qui, J.; Wang, J. Q.; Sharaf, J.; Zou, J.; Weiss, R.; Huang, H.; Joseph, W. J.; Ng, L.; Rosen, R.; Shen, B.; Reid, M. W.; Forrest, D.; Abramson, D. H.; Singer, S.; Cobrinik, D.; Jhanwar, S. C.
Article Title: SKP2 activation by thyroid hormone receptor β2 bypasses Rb-dependent proliferation in Rb-deficient cells
Abstract: Germline RB1 mutations strongly predispose humans to cone precursor–derived retinoblastomas and strongly predispose mice to pituitary tumors, yet shared cell type–specific circuitry that sensitizes these different cell types to the loss of RB1 has not been defined. Here we show that the cell type–restricted thyroid hormone receptor isoform TRb2 sensitizes to RB1 loss in both settings by antagonizing the widely expressed and tumor-suppressive TRb1. TRb2 promoted expression of the E3 ubiquitin ligase SKP2, a critical factor for RB1-mutant tumors, by enabling EMI1/FBXO5–dependent inhibition of SKP2 degradation. In RB1 wild-type neuroblastoma cells, endogenous Rb or ectopic TRb2 was required to sustain SKP2 expression as well as cell viability and proliferation. These results suggest that in certain contexts, Rb loss enables TRb1-dependent suppression of SKP2 as a safeguard against RB1-deficient tumorigenesis. TRb2 counteracts TRb1, thus disrupting this safeguard and promoting development of RB1-deficient malignancies. © 2017 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 77
Issue: 24
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2017-12-01
Start Page: 6838
End Page: 6850
Language: English
DOI: 10.1158/0008-5472.can-16-3299
PROVIDER: scopus
PMCID: PMC5732859
PUBMED: 28972075
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. David H Abramson
    254 Abramson
  2. Samuel Singer
    229 Singer
  3. Xiaoliang Xu
    15 Xu
  4. Suresh C Jhanwar
    212 Jhanwar
  5. Renbing Jia
    3 Jia
  6. Walter John Joseph
    14 Joseph
  7. David Chitty
    1 Chitty
  8. Aihong Ellen Liu
    1 Liu
  9. Jake Sharaf
    1 Sharaf
  10. Justin Wang
    1 Wang
  11. Hongyan Huang
    1 Huang
  12. Jianping Qui
    1 Qui