Cyclin C is a haploinsufficient tumour suppressor

Na Li; Anne Fassl; Joel Chick; Hiroyuki Inuzuka; Xiaoyu Li; Marc R. Mansour; Lijun Liu; Haizhen Wang; Bryan King; Shavali Shaik; Alejandro Gutierrez; Alban Ordureau; Tobias Otto; Taras Kreslavsky; Lukas Baitsch; Leah Bury; Clifford A. Meyer; Nan Ke; Kristin A. Mulry; Michael J. Kluk; Moni Roy; Sunkyu Kim; Xiaowu Zhang; Yan Geng; Agnieszka Zagozdzon; Sarah Jenkinson; Rosemary E. Gale; David C. Linch; Jean J. Zhao; Charles G. Mullighan; J. Wade Harper; Jon C. Aster; Iannis Aifantis; Harald Von Boehmer; Steven P. Gygi; Wenyi Wei; A. Thomas Look; Piotr Sicinski

doi:10.1038/ncb3046

Cyclin C is a haploinsufficient tumour suppressor

Na Li, Anne Fassl, Joel Chick, Hiroyuki Inuzuka, Xiaoyu Li, Marc R. Mansour, Lijun Liu, Haizhen Wang, Bryan King, Shavali Shaik, Alejandro Gutierrez, Alban Ordureau, Tobias Otto, Taras Kreslavsky, Lukas Baitsch, Leah Bury, Clifford A. Meyer, Nan Ke, Kristin A. Mulry, Michael J. KlukMoni Roy, Sunkyu Kim, Xiaowu Zhang, Yan Geng, Agnieszka Zagozdzon, Sarah Jenkinson, Rosemary E. Gale, David C. Linch, Jean J. Zhao, Charles G. Mullighan, J. Wade Harper, Jon C. Aster, Iannis Aifantis, Harald Von Boehmer, Steven P. Gygi, Wenyi Wei, A. Thomas Look, Piotr Sicinski

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Abstract

Cyclin C was cloned as a growth-promoting G 1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.

Original language	English (US)
Pages (from-to)	1080-1091
Number of pages	12
Journal	Nature cell biology
Volume	16
Issue number	11
DOIs	https://doi.org/10.1038/ncb3046
State	Published - Oct 31 2014
Externally published	Yes

ASJC Scopus subject areas

Cell Biology

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Li, N, Fassl, A, Chick, J, Inuzuka, H, Li, X, Mansour, MR, Liu, L, Wang, H, King, B, Shaik, S, Gutierrez, A, Ordureau, A, Otto, T, Kreslavsky, T, Baitsch, L, Bury, L, Meyer, CA, Ke, N, Mulry, KA, Kluk, MJ, Roy, M, Kim, S, Zhang, X, Geng, Y, Zagozdzon, A, Jenkinson, S, Gale, RE, Linch, DC, Zhao, JJ, Mullighan, CG, Harper, JW, Aster, JC, Aifantis, I, Von Boehmer, H, Gygi, SP, Wei, W, Look, AT & Sicinski, P 2014, 'Cyclin C is a haploinsufficient tumour suppressor', Nature cell biology, vol. 16, no. 11, pp. 1080-1091. https://doi.org/10.1038/ncb3046

@article{64bcd91b72734172bc7f086bd9d1fed3,

title = "Cyclin C is a haploinsufficient tumour suppressor",

abstract = "Cyclin C was cloned as a growth-promoting G 1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.",

author = "Na Li and Anne Fassl and Joel Chick and Hiroyuki Inuzuka and Xiaoyu Li and Mansour, {Marc R.} and Lijun Liu and Haizhen Wang and Bryan King and Shavali Shaik and Alejandro Gutierrez and Alban Ordureau and Tobias Otto and Taras Kreslavsky and Lukas Baitsch and Leah Bury and Meyer, {Clifford A.} and Nan Ke and Mulry, {Kristin A.} and Kluk, {Michael J.} and Moni Roy and Sunkyu Kim and Xiaowu Zhang and Yan Geng and Agnieszka Zagozdzon and Sarah Jenkinson and Gale, {Rosemary E.} and Linch, {David C.} and Zhao, {Jean J.} and Mullighan, {Charles G.} and Harper, {J. Wade} and Aster, {Jon C.} and Iannis Aifantis and {Von Boehmer}, Harald and Gygi, {Steven P.} and Wenyi Wei and Look, {A. Thomas} and Piotr Sicinski",

year = "2014",

month = oct,

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doi = "10.1038/ncb3046",

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T1 - Cyclin C is a haploinsufficient tumour suppressor

AU - Li, Na

AU - Fassl, Anne

AU - Chick, Joel

AU - Inuzuka, Hiroyuki

AU - Li, Xiaoyu

AU - Mansour, Marc R.

AU - Liu, Lijun

AU - Wang, Haizhen

AU - King, Bryan

AU - Shaik, Shavali

AU - Gutierrez, Alejandro

AU - Ordureau, Alban

AU - Otto, Tobias

AU - Kreslavsky, Taras

AU - Baitsch, Lukas

AU - Bury, Leah

AU - Meyer, Clifford A.

AU - Ke, Nan

AU - Mulry, Kristin A.

AU - Kluk, Michael J.

AU - Roy, Moni

AU - Kim, Sunkyu

AU - Zhang, Xiaowu

AU - Geng, Yan

AU - Zagozdzon, Agnieszka

AU - Jenkinson, Sarah

AU - Gale, Rosemary E.

AU - Linch, David C.

AU - Zhao, Jean J.

AU - Mullighan, Charles G.

AU - Harper, J. Wade

AU - Aster, Jon C.

AU - Aifantis, Iannis

AU - Von Boehmer, Harald

AU - Gygi, Steven P.

AU - Wei, Wenyi

AU - Look, A. Thomas

AU - Sicinski, Piotr

PY - 2014/10/31

Y1 - 2014/10/31

N2 - Cyclin C was cloned as a growth-promoting G 1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.

AB - Cyclin C was cloned as a growth-promoting G 1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.

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U2 - 10.1038/ncb3046

DO - 10.1038/ncb3046

M3 - Article

C2 - 25344755

AN - SCOPUS:84908489045

SN - 1465-7392

VL - 16

SP - 1080

EP - 1091

JO - Nature cell biology

JF - Nature cell biology

IS - 11

ER -

Cyclin C is a haploinsufficient tumour suppressor

Abstract

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