Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

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Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. / Krönke, Jan; Fink, Emma C.; Hollenbach, Paul W.; MacBeth, Kyle J.; Hurst, Slater N.; Udeshi, Namrata D.; Chamberlain, Philip P.; Mani, D. R.; Man, Hon Wah; Gandhi, Anita K.; Svinkina, Tanya; Schneider, Rebekka K.; McConkey, Marie; Järås, Marcus; Griffiths, Elizabeth; Wetzler, Meir; Bullinger, Lars; Cathers, Brian E.; Carr, Steven A.; Chopra, Rajesh; Ebert, Benjamin L.

I: Nature, Vol. 523, Nr. 7559, 09.07.2015, s. 183-188.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Krönke, J, Fink, EC, Hollenbach, PW, MacBeth, KJ, Hurst, SN, Udeshi, ND, Chamberlain, PP, Mani, DR, Man, HW, Gandhi, AK, Svinkina, T, Schneider, RK, McConkey, M, Järås, M, Griffiths, E, Wetzler, M, Bullinger, L, Cathers, BE, Carr, SA, Chopra, R & Ebert, BL 2015, 'Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS', Nature, vol. 523, nr. 7559, s. 183-188. https://doi.org/10.1038/nature14610

APA

Krönke, J., Fink, E. C., Hollenbach, P. W., MacBeth, K. J., Hurst, S. N., Udeshi, N. D., ... Ebert, B. L. (2015). Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature, 523(7559), 183-188. https://doi.org/10.1038/nature14610

CBE

Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, Chamberlain PP, Mani DR, Man HW, Gandhi AK, Svinkina T, Schneider RK, McConkey M, Järås M, Griffiths E, Wetzler M, Bullinger L, Cathers BE, Carr SA, Chopra R, Ebert BL. 2015. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 523(7559):183-188. https://doi.org/10.1038/nature14610

MLA

Vancouver

Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015 jul 9;523(7559):183-188. https://doi.org/10.1038/nature14610

Author

Krönke, Jan ; Fink, Emma C. ; Hollenbach, Paul W. ; MacBeth, Kyle J. ; Hurst, Slater N. ; Udeshi, Namrata D. ; Chamberlain, Philip P. ; Mani, D. R. ; Man, Hon Wah ; Gandhi, Anita K. ; Svinkina, Tanya ; Schneider, Rebekka K. ; McConkey, Marie ; Järås, Marcus ; Griffiths, Elizabeth ; Wetzler, Meir ; Bullinger, Lars ; Cathers, Brian E. ; Carr, Steven A. ; Chopra, Rajesh ; Ebert, Benjamin L. / Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. I: Nature. 2015 ; Vol. 523, Nr. 7559. s. 183-188.

RIS

TY - JOUR

T1 - Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

AU - Krönke, Jan

AU - Fink, Emma C.

AU - Hollenbach, Paul W.

AU - MacBeth, Kyle J.

AU - Hurst, Slater N.

AU - Udeshi, Namrata D.

AU - Chamberlain, Philip P.

AU - Mani, D. R.

AU - Man, Hon Wah

AU - Gandhi, Anita K.

AU - Svinkina, Tanya

AU - Schneider, Rebekka K.

AU - McConkey, Marie

AU - Järås, Marcus

AU - Griffiths, Elizabeth

AU - Wetzler, Meir

AU - Bullinger, Lars

AU - Cathers, Brian E.

AU - Carr, Steven A.

AU - Chopra, Rajesh

AU - Ebert, Benjamin L.

PY - 2015/7/9

Y1 - 2015/7/9

N2 - Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4CRBN. These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.

AB - Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4CRBN. These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.

UR - http://www.scopus.com/inward/record.url?scp=84936930551&partnerID=8YFLogxK

U2 - 10.1038/nature14610

DO - 10.1038/nature14610

M3 - Article

VL - 523

SP - 183

EP - 188

JO - Nature

T2 - Nature

JF - Nature

SN - 0028-0836

IS - 7559

ER -