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ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice
Mathew C. Casimiro, … , Andrew Arnold, Richard G. Pestell
Mathew C. Casimiro, … , Andrew Arnold, Richard G. Pestell
Published February 6, 2012
Citation Information: J Clin Invest. 2012;122(3):833-843. https://doi.org/10.1172/JCI60256.
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Research Article Oncology Article has an altmetric score of 14

ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice

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Abstract

Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1–/– mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1–rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland–targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.

Authors

Mathew C. Casimiro, Marco Crosariol, Emanuele Loro, Adam Ertel, Zuoren Yu, William Dampier, Elizabeth A. Saria, Alex Papanikolaou, Timothy J. Stanek, Zhiping Li, Chenguang Wang, Paolo Fortina, Sankar Addya, Aydin Tozeren, Erik S. Knudsen, Andrew Arnold, Richard G. Pestell

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Figure 4

Cyclin D1 induces centrosome amplification and mitotic spindle disorganization.

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Cyclin D1 induces centrosome amplification and mitotic spindle disorgani...
(A and C) Representative confocal maximum Z projections of mitotic cells (A; immunostained for α-tubulin [violet] and DAPI [blue]) and prophase, prometaphase, and metaphases (C; immunostained for α-tubulin [violet], γ-tubulin [yellow], and DAPI [blue and insets]) from control and cyclin D1–rescued Ccnd1–/– cells. Original magnification, ×60 NA1.4 oil objective, enlarged ×5 by digital zoom. Scale bars: 5 μm. (B and D) Frequency of mitotic cells with multiple polar spindles (B) and of prometaphase/metaphase cells with multiple centrosomes (γ-tubulin) and spindle disorganization (α-tubulin) (D). *P = 0.0289, χ2 analysis. Black bar, abnormal centrosome count (i.e., >2); gray bar, normal count (i.e., 2). (E and F) Spindle measurements on maximum Z projections of metaphase control and cyclin D1–rescued Ccnd1–/– cells. Data are mean ± SEM. Insets demonstrate metaphase plate (i.e., chromatin; Ch) width and length (measured using DAPI stain) and spindle (Sp) width and length (measured using tubulin stain). *P = 0.0486; **P = 0.0087.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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