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Modulation of CDK2-AP1 (p12DOC−1) expression in human colorectal cancer

Oncogene volume 24, pages 3657–3668 (2005)Cite this article

Abstract

We have previously demonstrated an association between microsatellite instability and decreased CDK2-AP1 (p12DOC−1) expression in human colorectal cancer (CRC) cell lines. In those same studies, induction of CDK2-AP1 expression promoted both cell cycle arrest and apoptosis. The goals of our present study were to better understand the mechanisms leading to reduced CDK2-AP1 expression in microsatellite unstable (MSI) CRC and to study further the effect of CDK2-AP1 modulation on cell proliferation and apoptosis utilizing RNA interference (RNAi) techniques. We used direct sequencing to screen for mutations of the poly (T)8 microsatellite-like region in the 3′ end of the CDK2-AP1 gene in 24 CRC cell lines. We then utilized an in vitro human mismatch repair (MMR) recombinant system to assess for correction of the mutation and changes in CDK2-AP1 expression secondary to hMLH1 transfection. We also investigated the effect of CDK2-AP1 modulation in four settings: (1) native CDK2-AP1 absence, (2) endogenous CDK2-AP1 expression, (3) RNAi-induced CDK2-AP1 inhibition and (4) induced CDK2-AP1 over expression. The mutation – del T poly (T)8 – at the 3′ end of the CDK2-AP1 gene was found in 3/12 (25%) of MSI CRC cell lines, but in none of the microsatellite stable samples (0/12). Interestingly, when wild-type MMR protein – MLH1 – was induced in an in vitro human recombinant system, the del T poly (T)8 mutation was reversed and CDK2-AP1 expression increased. RNAi-mediated CDK2-AP1 inhibition was associated with decreased apoptosis and increased cell proliferation in CDK2-AP1-non deficient CRC cell lines. We conclude that mutations in the microsatellite-like sequence of the CDK2-AP1 gene in MSI CRC are associated with decreased CDK2-AP1 expression. In addition, modulation of CDK2-AP1 expression in human CRC alters cell proliferation and apoptosis.

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Acknowledgements

This work was supported in part by an Albert Einstein Cancer Center support grant to Thomas K. Weber.

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Authors and Affiliations

  1. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 707, New York, NY, 10461, USA

    Ziquan Yuan & Thomas K Weber

  2. Department of Medical Oncology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 707, New York, NY, 10461, USA

    Anu G Gaba

  3. Department of Surgery, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 707, New York, NY, 10461, USA

    Tara Sotsky Kent, Anna Bennett & Thomas K Weber

  4. Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 707, New York, NY, 10461, USA

    Agnes Miller

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  1. Ziquan Yuan
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Correspondence to Thomas K Weber.

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Yuan, Z., Gaba, A., Kent, T. et al. Modulation of CDK2-AP1 (p12DOC−1) expression in human colorectal cancer. Oncogene 24, 3657–3668 (2005). https://doi.org/10.1038/sj.onc.1208378

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