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Citations to this article

The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells
Uta Kossatz, … , Jeffrey D. Singer, Nisar P. Malek
Uta Kossatz, … , Jeffrey D. Singer, Nisar P. Malek
Published October 11, 2010
Citation Information: J Clin Invest. 2010;120(11):3820-3833. https://doi.org/10.1172/JCI41959.
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Research Article Oncology Article has an altmetric score of 3

The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells

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Abstract

Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent substantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice. In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas. Importantly, loss of Cul3 expression was also detected in a large series of human liver cancers and correlated directly with tumor de-differentiation. The expression of Cul3 during hepatic differentiation therefore safeguards against the formation of progenitor cells that carry a great potential for transformation into tumor-initiating cells.

Authors

Uta Kossatz, Kai Breuhahn, Benita Wolf, Matthias Hardtke-Wolenski, Ludwig Wilkens, Doris Steinemann, Stephan Singer, Felicitas Brass, Stefan Kubicka, Brigitte Schlegelberger, Peter Schirmacher, Michael P. Manns, Jeffrey D. Singer, Nisar P. Malek

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Total citations by year

Year: 2025 2024 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 Total
Citations: 1 3 1 3 4 1 4 2 2 3 2 6 3 1 36
Citation information
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Citations to this article (36)

Title and authors Publication Year
Iron metabolism in a mouse model of hepatocellular carcinoma
Yilmaz D, Tharehalli U, Paganoni R, Knoop P, Gruber A, Chen Y, Dong R, Leithäuser F, Seufferlein T, Leopold K, Lechel A, Vujić Spasić M
Scientific Reports 2025
Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.
Gu L, Du Y, Chen J, Hasan MN, Clayton YD, Matye DJ, Friedman JE, Li T
Proceedings of the National Academy of Sciences 2024
Integrative Bioinformatics Analysis Reveals Potential Target Genes and PTEN Signaling in Breast Cancer and Effect of Zingiber officinale (Ginger) and Allium sativum (Garlic) extract on It
Sheybatzadeh K, Moshtaghie SA, Shahanipour K, Golab F
Asian Pacific Journal of Cancer Prevention 2024
Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics
Wu W, Wang X, Ma R, Huang S, Li H, Lyu X
Genes & Diseases 2024
Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization.
Chen C, Gu L, Matye DJ, Clayton YD, Hasan MN, Wang Y, Friedman JE, Li T
Proceedings of the National Academy of Sciences 2022
Cyclin E in normal physiology and disease states
C Chu, Y Geng, Y Zhou, P Sicinski
Trends in Cell Biology 2021
Cul3 is required for normal development of the mammary gland
CM Cummings, JD Singer
Cell and Tissue Research 2021
Cullin3 deficiency shapes tumor microenvironment and promotes cholangiocarcinoma in liver-specific Smad4/Pten mutant mice
M Zhao, Y Quan, J Zeng, X Lyu, H Wang, JH Lei, Y Feng, J Xu, Q Chen, H Sun, X Xu, L Lu, CX Deng
International journal of biological sciences 2021
The diverse roles of SPOP in prostate cancer and kidney cancer
Z Wang, Y Song, M Ye, X Dai, X Zhu, W Wei
Nature Reviews Urology 2020
Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells
AP Drainas, RA Lambuta, I Ivanova, Ö Serçin, I Sarropoulos, ML Smith, T Efthymiopoulos, B Raeder, AM Stütz, SM Waszak, BR Mardin, JO Korbel
Cell Reports 2020
Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure
J Wu, JA McCormick, CD Sigmund
Current Hypertension Reports 2020
Functional Genomic Screening Independently Identifies CUL3 as a Mediator of Vemurafenib Resistance via Src-Rac1 Signaling Axis
M Vanneste, CR Feddersen, A Varzavand, EY Zhu, T Foley, L Zhao, KH Holt, M Milhem, R Piper, CS Stipp, AJ Dupuy, MD Henry
Frontiers in Oncology 2020
Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis
T Saritas, CA Cuevas, MZ Ferdaus, C Kuppe, R Kramann, MJ Moeller, J Floege, JD Singer, JA McCormick
Scientific Reports 2019
Functional analysis of Cullin 3 E3 ligases in tumorigenesis
J Cheng, J Guo, Z Wang, BJ North, K Tao, X Dai, W Wei
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2018
Regulation of cyclin E1 expression in human pluripotent stem cells and derived neural progeny
MS Varela, S Mucci, GA Richardson, OM Hanon, VA Furmento, SG Miriuka, GE Sevlever, ME Scassa, L Romorini
Cell cycle (Georgetown, Tex.) 2018
Dishevelled: A masterful conductor of complex Wnt signals
M Sharma, I Castro-Piedras, GE Simmons, K Pruitt
Cellular Signalling 2018
Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway
RJ Cornelius, J Si, CA Cuevas, JW Nelson, BD Gratreak, R Pardi, CL Yang, DH Ellison
Journal of the American Society of Nephrology : JASN 2018
KCTD2, an adaptor of Cullin3 E3 ubiquitin ligase, suppresses gliomagenesis by destabilizing c-Myc
EJ Kim, SH Kim, X Jin, X Jin, H Kim
Cell Death and Differentiation 2017
Metabolic enzymes: key modulators of functionality in cancer stem-like cells
BW Dong, GM Qin, Y Luo, JS Mao
Oncotarget 2017
Maitake Pro4X has anti-cancer activity and prevents oncogenesis in BALBc mice
A Roldan-Deamicis, E Alonso, B Brie, DA Braico, GA Balogh
Cancer Medicine 2016
Cullin3–KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression
C Zhang, J Liu, G Huang, Y Zhao, X Yue, H Wu, J Li, J Zhu, Z Shen, BG Haffty, W Hu, Z Feng
Genes & development 2016
Cullin Family Proteins and Tumorigenesis: Genetic Association and Molecular Mechanisms
Z Chen, J Sui, F Zhang, C Zhang
Journal of Cancer 2015
DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase
H Bi, S Li, X Qu, M Wang, X Bai, Z Xu, X Ao, Z Jia, X Jiang, Y Yang, H Wu
Cell Death and Disease 2015
Cullin3 promotes breast cancer cells metastasis and epithelial-mesenchymal transition by targeting BRMS1 for degradation
Huo X, Li S, Shi T, Suo A, Ruan Z, Guo H, Yao Y
Oncotarget 2015
Mutant CUL3 degrades KLHL3 to promote WNK signaling in hyperkalemic hypertension
James A. McCormick, Chao-Ling yang, Chong Zhang, Brittney Davidge, Blankenstein Katharina, Andrew Terker, Bethzaida Yarbrough, Nicholas Meermeier, Hae-Jean Park, Belinda McCully, Mark West, Aljona Borschewski, Nina Himmerkus, Markus Bleich, Sebastian Bachmann, Kerim Mutig, Eduardo Argaiz, Gerardo Gamba, Jeffrey Singer, David H. Ellison
Journal of Clinical Investigation 2014
Structure–activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein–protein interaction inhibitors
K Takrouri, T Chen, E Papadopoulos, R Sahoo, E Kabha, H Chen, S Cantel, G Wagner, JA Halperin, BH Aktas, M Chorev
European Journal of Medicinal Chemistry 2014
Genes Related to Suppression of Malignant Phenotype Induced by Maitake D-Fraction in Breast Cancer Cells
EN Alonso, M Orozco, AE Nieto, GA Balogh
Journal of Medicinal Food 2013
Molecular Mechanisms of Fibrosis-Associated Promotion of Liver Carcinogenesis
T Uehara, GR Ainslie, K Kutanzi, IP Pogribny, L Muskhelishvili, T Izawa, J Yamate, O Kosyk, S Shymonyak, BU Bradford, GA Boorman, R Bataller, I Rusyn
Toxicological Sciences 2013
The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications
P Genschik, I Sumara, E Lechner
The EMBO Journal 2013
Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases
W Zhou, W Wei, Y Sun
Cell Research 2013
Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism
Y Xu, KL Swartz, KT Siu, M Bhattacharyya, AC Minella
Oncogene 2013
Cullin 3 as a novel target in diverse pathologies
AC Andérica-Romero, IG González-Herrera, A Santamaría, J Pedraza-Chaverri
Redox Biology 2013
Cullin-3 Regulates Vascular Smooth Muscle Function and Arterial Blood Pressure via PPARγ and RhoA/Rho-Kinase
CJ Pelham, P Ketsawatsomkron, S Groh, JL Grobe, WJ de Lange, SR Ibeawuchi, HL Keen, ET Weatherford, FM Faraci, CD Sigmund
Cell Metabolism 2012
High expression of cancer stem cell markers in cholangiolocellular carcinoma
S Iwahashi, T Utsunomiya, M Shimada, Y Saito, Y Morine, S Imura, T Ikemoto, H Mori, J Hanaoka, Y Bando
Surgery Today 2012
An integrated view of cyclin E function and regulation
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Cell cycle (Georgetown, Tex.) 2012
Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway
P Viatour, U Ehmer, LA Saddic, C Dorrell, JB Andersen, C Lin, AF Zmoos, PK Mazur, BE Schaffer, A Ostermeier, H Vogel, KG Sylvester, SS Thorgeirsson, M Grompe, J Sage
Journal of Experimental Medicine 2011

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