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Deregulated minichromosomal maintenance protein MCM7 contributes to oncogene driven tumorigenesis

Abstract

Minichromosomal maintenance protein 7 (MCM7) is an essential component of the replication helicase complex (MCM2-7) required for DNA replication. Although this function is highly conserved among eukaryotes, additional functions for the MCM molecules continue to be described. Minichromosomal maintenance protein 7 is a marker for proliferation and is upregulated in a variety of tumors including neuroblastoma, prostate, cervical and hypopharyngeal carcinomas. To further investigate the general role of MCM7 in tumorigenesis, we generated a mouse model with deregulated MCM7 expression targeted to the basal layer of the epidermis using the keratin 14 (K14) promoter (K14.MCM7). When subjected to a two-stage chemical carcinogenesis protocol (dimethylbenz[α]anthracene (DMBA) initiation with 12-ortho-tetradecanoylphorbol-13-acetate promotion), K14.MCM7 mice showed significantly increased incidence and prevalence of tumor development relative to controls. Furthermore, within 40 weeks of treatment over 45% K14.MCM7 mice exhibited tumors that had converted to squamous cell carcinomas versus none in the control group. As predicted from previous skin carcinogenesis studies using DMBA as the initiating agent, Ras mutations where found in more than 90% of tumors isolated from K14.MCM7 mice. Whereas previous studies have shown that MCM7 is useful as a proliferation marker, our data suggest that deregulated MCM7 expression actively contributes to tumor formation, progression and malignant conversion.

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Abbreviations

K14:

keratin 14

SCC:

squamous cell carcinoma

DMBA:

dimethylbenz[α]anthracene

TPA:

12-ortho-tetradecanoylphorbol-13-acetate

HNSCC, head and neck squamous cell carcinomaMCM7:

mimichromosomal maintenance protein 7 (cdc47)

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Acknowledgements

We thank Dr Tohru Kiyono for the human MCM7 cDNA and Dr Timothy McDonnell for help with the histopathology of the chemically derived tumors. JMS gratefully acknowledges the generous support from the Hope Street Kids foundation and the Logenbaugh foundation and is supported by NIH Grant KO-8 CA90517-02 (JMS).

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Correspondence to J M Shohet.

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Honeycutt, K., Chen, Z., Koster, M. et al. Deregulated minichromosomal maintenance protein MCM7 contributes to oncogene driven tumorigenesis. Oncogene 25, 4027–4032 (2006). https://doi.org/10.1038/sj.onc.1209435

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