Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle

Búa, Sabela S; Sotiropoulou, Panagiota A.; Sgarlata, Cecilia; Borlado, Luis R.; Eguren, Manuel; Domı́nguez, Orlando; Ortega, Sagrario; Malumbres, Marcos; Blanpain, Cédric; Méndez, Juan Pablo

doi:10.1080/15384101.2015.1120919

Cited by 14 publications

(10 citation statements)

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“…Indeed, overexpression of Cdc6 and Cdt1 in pre-malignant cells promotes malignant behavior (Liontos et al, 2007), and both factors are overexpressed in several tumor types (reviewed by Petrakis et al, 2016). Transgenic mice expressing Cdt1 in thymocytes are prone to lymphoblastic lymphomas (Seo et al, 2005), and transgenic mice expressing Cdc6 in the skin are prone to papillomas (Bú a et al, 2015). In p53 mutant cancer cells that proliferate despite expressing CDK inhibitor p21, genomic instability has been linked to the deregulation of CDC6 and CDT1 proteins (Galanos et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

et al. 2017

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Mammalian DNA replication origins are "licensed" by the loading of DNA helicases, a reaction that is mediated by CDC6 and CDT1 proteins. After initiation of DNA synthesis, CDC6 and CDT1 are inhibited to prevent origin reactivation and DNA overreplication before cell division. CDC6 and CDT1 are highly expressed in many types of cancer cells, but the impact of their deregulated expression had not been investigated in vivo. Here, we have generated mice strains that allow the conditional overexpression of both proteins. Adult mice were unharmed by the individual overexpression of either CDC6 or CDT1, but their combined deregulation led to DNA re-replication in progenitor cells and lethal tissue dysplasias. This study offers mechanistic insights into the necessary cooperation between CDC6 and CDT1 for facilitation of origin reactivation and describes the physiological consequences of DNA overreplication.

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Section: Introductionmentioning

confidence: 99%

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

et al. 2017

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“…In accordance with these findings, overexpression of the replication licensing factors Cdt1 and Cdc6 has been reported to promote rereplication and the DDR, whereas their overexpression in premalignant cells leads to transformation and tumor development . Cdc6 has also been shown to induce papilloma formation in the mouse , whereas Mcm7‐overexpressing mice developed squamous cell carcinomas , both in the presence of mutagenic agents.…”

Section: Resultsmentioning

confidence: 52%

Geminin ablation in vivo enhances tumorigenesis through increased genomic instability

Tsaniras

Villiou

Giannou

et al. 2018

The Journal of Pathology

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Geminin, a DNA replication licensing inhibitor, ensures faithful DNA replication in vertebrates. Several studies have shown that geminin depletion in vitro results in rereplication and DNA damage, whereas increased expression of geminin has been observed in human cancers. However, conditional inactivation of geminin during embryogenesis has not revealed any detectable DNA replication defects. In order to examine its role in vivo, we conditionally inactivated geminin in the murine colon and lung, and assessed chemically induced carcinogenesis. We show here that mice lacking geminin develop a significantly higher number of tumors and bear a larger tumor burden than sham-treated controls in urethane-induced lung and azoxymethane/dextran sodium sulfate-induced colon carcinogenesis. Survival is also significantly reduced in mice lacking geminin during lung carcinogenesis. A significant increase in the total number and grade of lesions (hyperplasias, adenomas, and carcinomas) was also confirmed by hematoxylin and eosin staining. Moreover, increased genomic aberrations, identified by increased ATR and γH2AX expression, was detected with immunohistochemistry analysis. In addition, we analyzed geminin expression in human colon cancer, and found increased expression, as well as a positive correlation with ATM/ATR levels and a non-monotonic association with γH2AX. Taken together, our data demonstrate that geminin acts as a tumor suppressor by safeguarding genome stability, whereas its overexpression is also associated with genomic instability. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Overexpression of CDC6 has been reported in a variety of cancers [ 20 , 21 ]. CDC6 is an essential initiation protein for DNA replication, playing a vital role in tumorigenesis by regulating cell cycle, apoptosis, and invasion [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Mir-26b inhibits growth and resistance to paclitaxel chemotherapy by silencing the CDC6 gene in gastric cancer

Zhao

Chen

et al. 2019

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A b s t r a c tIntroduction: Gastric cancer is one of the most common cancers of the digestive system and is associated with high morbidity and mortality. The aim of this study was to investigate whether miR-26b is involved in the proliferation and resistance to paclitaxel chemotherapy in gastric cancer cells. Material and methods: The expression of miR-26b in gastric cancer cell lines was determined by quantitative real-time PCR. Bioinformatics software was used to predict potential target genes of miR-26b. Luciferase assay was used to verify the interactions between target genes and miR-26b. CDC6 protein expression was measured by Western blot. The proliferation and chemotherapy resistance were analyzed by MTT assay. Cell invasion was evaluated by Transwell assay. Results: MiR-26b was down-regulated in gastric cancer cell lines compared to normal control cells, and its expression in drug resistance cells was even lower (p < 0.05). CDC6 was identified as a potential target gene of miR-26b by using bioinformatics analysis software. The expression of CDC6 was inhibited by miR-26b both at RNA level, which was determined by luciferase assay, and at protein level, which was determined by Western blot (p < 0.05). Silencing CDC6 inhibited cell proliferation, invasion, and promoted apoptosis of gastric cancer cell lines, BGC823 and SGC7901 (p < 0.05). Moreover, CDC6 knockdown inhibited chemotherapy resistance to paclitaxel, IC50 to paclitaxel decreased from 153.17 ±0.49 μg/l to 39.81 ±0.28 μg/l (p < 0.05). Conclusions: miR-26b inhibits growth and resistance to paclitaxel chemotherapy by silencing the CDC6 gene in the gastric cancer cell line SGC7901.

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Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle

Cited by 14 publications

References 52 publications

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

In Vivo DNA Re-replication Elicits Lethal Tissue Dysplasias

Geminin ablation in vivo enhances tumorigenesis through increased genomic instability

Mir-26b inhibits growth and resistance to paclitaxel chemotherapy by silencing the CDC6 gene in gastric cancer

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