Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

Casimiro, Mathew C.; Sante, Gabriele Di; Crosariol, Marco; Loro, Emanuele; Dampier, William; Ertel, Adam; Yu, Zuoren; Saria, Elizabeth A.; Παπανικολάου, Αλέξανδρος; Li, Zhiping; Wang, Chenguang; Addya, Sankar; Lisanti, Michael P.; Fortina, Paolo; Cardiff, Robert D.; Tözeren, Aydın; Knudsen, Erik S.; Arnold, Andrew; Pestell, Richard G.

doi:10.18632/oncotarget.3267

Cited by 41 publications

(50 citation statements)

References 49 publications

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“…Autophagy limits genomic instability and the inhibition of this autophagic function increases genomic instability (49). The inhibition of autophagy by cyclin D1 is therefore consistent with the known effects of cyclin D1 to induce chromosomal instability (13,20). The current studies extend the reported cyclin D1 functions that may contribute to the collaborative oncogenic function of cyclin D1.…”

Section: Discussionsupporting

confidence: 84%

“…CCND1 is overexpressed in a variety of malignancies and is increased in the early phase of breast cancer malignancy, including ductal carcinoma in situ (12). In recent studies of transgenic mice, cyclin D1 mediated promotion of breast tumorigenesis was kinase-independent, but autophagy restraint was kinase-dependent raising the question of the molecular mechanisms governing autophagy restraint (13,14). The current studies confirmed these prior findings and extended these observations to identify the molecular mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis

et al. 2017

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Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclinD1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that Cyclin D1 inhibited mitochondrial function, promoted glycolysis and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis

et al. 2017

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“…Notably, the present study also identified that AEG1 silencing inhibits the expression of cyclin D1, c-Myc and MMP9. Previous studies suggested that cyclin D1and c-Myc are associated with cell proliferation, and are involved in tumorigenesis and deterioration (31)(32)(33). Cyclin D1 is a key protein that serves an essential role on the biologic effects of breast cancer cells, and the overexpression of the protein has been demonstrated to be associated with tumor stage, lymph node metastasis and a poor prognosis in breast cancer (34,35).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte elevated gene-1 promotes the proliferation and invasion of breast cancer cells by activating the Wnt/β-catenin signaling pathway

Dai

Wang

et al. 2017

Oncology Letters

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Abstract. Astrocyte elevated gene-1 (AEG1) was identified to be overexpressed in breast cancer, and to be associated with the development of breast cancer. In the present study, AEG1 was identified as highly expressed in the MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cell lines and was detected in the MCF-10A normal breast epithelial cell line. The present study established an AEG1-knockdown MCF-7 cell line to investigate the expression status of certain cancer-associated proteins. Western blotting demonstrated that AEG1 may affect cancer cell proliferation and invasion via activating the Wnt/β-catenin signaling pathway, a hypothesis that has been supported by cell function tests. The results of the present study demonstrated that when AEG1 was significantly overexpressed in breast cancer cells it promoted cell proliferation and invasion via activating the Wnt/β-catenin signaling pathway. Therefore, AEG1 may serve as a novel therapeutic target in breast cancer. IntroductionBreast cancer is a common type of malignancy; the incidence of the disease has increased in recent years worldwide, currently ranking first with respect to cancer-associated morbidity in women (1-3). The traditional methods of treatment include surgery, radiotherapy and chemotherapy for patients with advanced breast cancer exhibit poor efficacy (4). Therefore, the development of gene-targeted therapy for breast cancer requires further attention. Previous studies have revealed that numerous genes are involved in the occurrence and development of breast cancer, including cyclin D1, matrix metalloproteinases (MMPs) and E-cadherin (5-8). Astrocyte elevated gene-1 (AEG1) has also been investigated with respect to poor prognosis in breast cancer (9). AEG1 is a potentially crucial mediator of tumor malignancy and a key converging point of a complex network of oncogenic signaling pathways (10-12). Previous studies revealed that the AEG1 gene was significantly overexpressed in a number of types of malignant cells, and is associated with tumorigenesis, proliferation, invasion and metastasis (13,14). Statistics also demonstrated that AEG1 was upregulated in breast cancer tissue and positively correlated with clinical stage and lymph node metastasis (15).The Wnt signaling pathway is one of the most important intracellular signal transduction pathways, and it affects the activated state of multiple effector molecules downstream (16)(17)(18)(19). It is closely associated with a variety of human tumor developments, and serves an important role in breast cancer cell proliferation and invasion (20,21). However, the mechanisms that underlie the activation of the Wnt signaling pathway in various types of breast cancer have yet to be identified. β-catenin has been revealed as a central regulator in the Wnt signaling pathway, and is associated with disease progression and poor prognosis in breast cancer (22). Typically, during activation of the Wnt signaling pathway, β-catenin accumulates in the cytosol at high levels, binds to T-cell factor/lymphoid enhancer fac...

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“…4,6 As cyclin D1 overexpression occurs frequently in human cancers 40,41 by gene amplification and alternative transcriptional up-regulation mechanisms [41][42][43] a better understanding of the redundancy between ATF2 and ATF7 should be of great interest.…”

Section: Discussionmentioning

confidence: 99%

ATF7 is stabilized during mitosis in a CDK1-dependent manner and contributes to cyclin D1 expression

et al. 2015

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The transcription factor ATF7 undergoes multiple post-translational modifications, each of which has distinct effects upon ATF7 function. Here, we show that ATF7 phosphorylation on residue Thr112 exclusively occurs during mitosis, and that ATF7 is excluded from the condensed chromatin. Both processes are CDK1/cyclin B dependent. Using a transduced neutralizing monoclonal antibody directed against the Thr112 epitope in living cells, we could demonstrate that Thr112 phosphorylation protects endogenous ATF7 protein from degradation, while it has no effect on the displacement of ATF7 from the condensed chromatin. The crucial role of Thr112 phosphorylation in stabilizing ATF7 protein during mitosis was confirmed using phospho-mimetic and phospho-deficient mutants. Finally, silencing ATF7 by CRISPR/Cas9 technology leads to a decrease of cyclin D1 protein expression levels. We propose that mitotic stabilized ATF7 protein re-localizes onto chromatin at the end of telophase and contributes to induce the cyclin D1 gene expression.

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Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis

Cited by 41 publications

References 49 publications

Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis

Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis

Astrocyte elevated gene-1 promotes the proliferation and invasion of breast cancer cells by activating the Wnt/β-catenin signaling pathway

ATF7 is stabilized during mitosis in a CDK1-dependent manner and contributes to cyclin D1 expression

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