Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion

S. Wei, X. Chen, K. McGraw, L. Zhang, R. Komrokji, J. Clark, G. Caceres, D. Billingsley, L. Sokol, J. Lancet, N. Fortenbery, J. Zhou, E. A. Eksioglu, D. Sallman, H. Wang, P. K. Epling-Burnette, J. Djeu, M. Sekeres, J. P. Maciejewski, A. List

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Abstract

Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of mouse double minute 2 protein (MDM2), with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide (Len) acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that Len inhibits the haplodeficient protein phosphatase 2A catalytic domain alpha (PP2Acα) phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS14 to suppress MDM2 autoubiquitination whereas PP2Acα overexpression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to Len overexpressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that Len restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.

Original languageEnglish (US)
Pages (from-to)1110-1120
Number of pages11
JournalOncogene
Volume32
Issue number9
DOIs
StatePublished - Feb 28 2013

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Chromosome Deletion
Ubiquitination
Myelodysplastic Syndromes
Protein Phosphatase 2
Catalytic Domain
Serine
Bone Marrow
Aplastic Anemia
Ribosomal Proteins
Gene Deletion
Ribosomes
Phosphoric Monoester Hydrolases
Drug Resistance
Protein Binding
Transcriptional Activation
lenalidomide
Mouse Mdm2 protein
Chromosome 5q Deletion Syndrome

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Wei, S. ; Chen, X. ; McGraw, K. ; Zhang, L. ; Komrokji, R. ; Clark, J. ; Caceres, G. ; Billingsley, D. ; Sokol, L. ; Lancet, J. ; Fortenbery, N. ; Zhou, J. ; Eksioglu, E. A. ; Sallman, D. ; Wang, H. ; Epling-Burnette, P. K. ; Djeu, J. ; Sekeres, M. ; Maciejewski, J. P. ; List, A. / Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. In: Oncogene. 2013 ; Vol. 32, No. 9. pp. 1110-1120.
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title = "Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion",
abstract = "Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of mouse double minute 2 protein (MDM2), with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide (Len) acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that Len inhibits the haplodeficient protein phosphatase 2A catalytic domain alpha (PP2Acα) phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS14 to suppress MDM2 autoubiquitination whereas PP2Acα overexpression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to Len overexpressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that Len restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.",
author = "S. Wei and X. Chen and K. McGraw and L. Zhang and R. Komrokji and J. Clark and G. Caceres and D. Billingsley and L. Sokol and J. Lancet and N. Fortenbery and J. Zhou and Eksioglu, {E. A.} and D. Sallman and H. Wang and Epling-Burnette, {P. K.} and J. Djeu and M. Sekeres and Maciejewski, {J. P.} and A. List",
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Wei, S, Chen, X, McGraw, K, Zhang, L, Komrokji, R, Clark, J, Caceres, G, Billingsley, D, Sokol, L, Lancet, J, Fortenbery, N, Zhou, J, Eksioglu, EA, Sallman, D, Wang, H, Epling-Burnette, PK, Djeu, J, Sekeres, M, Maciejewski, JP & List, A 2013, 'Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion', Oncogene, vol. 32, no. 9, pp. 1110-1120. https://doi.org/10.1038/onc.2012.139

Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. / Wei, S.; Chen, X.; McGraw, K.; Zhang, L.; Komrokji, R.; Clark, J.; Caceres, G.; Billingsley, D.; Sokol, L.; Lancet, J.; Fortenbery, N.; Zhou, J.; Eksioglu, E. A.; Sallman, D.; Wang, H.; Epling-Burnette, P. K.; Djeu, J.; Sekeres, M.; Maciejewski, J. P.; List, A.

In: Oncogene, Vol. 32, No. 9, 28.02.2013, p. 1110-1120.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion

AU - Wei, S.

AU - Chen, X.

AU - McGraw, K.

AU - Zhang, L.

AU - Komrokji, R.

AU - Clark, J.

AU - Caceres, G.

AU - Billingsley, D.

AU - Sokol, L.

AU - Lancet, J.

AU - Fortenbery, N.

AU - Zhou, J.

AU - Eksioglu, E. A.

AU - Sallman, D.

AU - Wang, H.

AU - Epling-Burnette, P. K.

AU - Djeu, J.

AU - Sekeres, M.

AU - Maciejewski, J. P.

AU - List, A.

PY - 2013/2/28

Y1 - 2013/2/28

N2 - Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of mouse double minute 2 protein (MDM2), with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide (Len) acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that Len inhibits the haplodeficient protein phosphatase 2A catalytic domain alpha (PP2Acα) phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS14 to suppress MDM2 autoubiquitination whereas PP2Acα overexpression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to Len overexpressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that Len restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.

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