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Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells

Oncogene volume 18, pages 103–115 (1999)Cite this article

Abstract

Recent studies have shown that decreased expression of p27Kip1 is associated with high grade tumors and an unfavorable prognosis in several types of human cancer. To clarify the role of p27Kip1 in colon cancer, we have overexpressed this protein in the HT29 colon cancer cell line. The derivatives displayed an increase in the p27Kip1 protein in cyclin E/CDK2 immunoprecipitates and a decrease in cyclin E-associated kinase activity when compared to vector control clones, providing evidence that the overexpressed protein was functional. Clones with a high level of p27Kip1 displayed partial growth inhibition in monolayer culture and a decrease in plating efficiency, even though they expressed increased levels of the cyclin D1 protein. Using alkaline phosphatase expression as a marker, we found that the p27Kip1 overexpressor clones displayed a 2 – 3-fold increase in sensitivity to induction of differentiation by 2 mM sodium butyrate. In contrast to these results, derivatives of HT29 cells that stably overexpressed p21Cip1/Waf1 displayed decreased sensitivity to the induction of differentiation. These findings may explain why decreased levels of p27Kip1 in certain human cancers is associated with high grade (poorly differentiated) tumors, and suggest that strategies that increase the level of p27Kip1 may be useful in cancer therapy.

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Abbreviations

p21:

p21Cip1/Waf1

p27:

p27Kip1

CDK:

cyclin-dependent kinase

CKI:

cyclin-dependent kinase inhibitor

CAK:

cyclin-dependent kinase-activating kinase

PAGE:

polyacrylamide gel electrophoresis

IAP:

intestinal alkaline phosphatase

FBS:

fetal bovine serum

SB:

sodium butyrate

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Acknowledgements

The authors wish to thank T Hunter and J Massague for providing human p21Cip1/Waf1 and p27Kip1 cDNAs, respectively. We are also grateful to E Okin for technical assistance, B Castro and P Jean-Louis for excellent assistance in the preparation of this manuscript and A Sgambato and M Ciaparrone for valuable discussion. This research was supported by an award for Cancer Research from the FUSO Pharmaceutical Company, Osaka, Japan (to HY); and by National Cancer Institute Grant CA 63467 and an award from the National Foundation for Cancer Research (to IBW).

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Authors and Affiliations

  1. Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, New York, 10032, NY, USA

    Hirofumi Yamamoto, Jae-Won Soh, Haim Shirin, Wang-Qiu Xing, Jin TE Lim, Yao Yao, Eric Slosberg & I Bernard Weinstein

  2. Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, New York, 10032, NY, USA

    Ira Schieren

  3. Department of Surgery II, Osaka University Medical School, 2-2, Yamadaoka, Suita, 565, Osaka, Japan

    Hirofumi Yamamoto & Naohiro Tomita

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  1. Hirofumi Yamamoto
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Yamamoto, H., Soh, JW., Shirin, H. et al. Comparative effects of overexpression of p27Kip1 and p21Cip1/Waf1 on growth and differentiation in human colon carcinoma cells. Oncogene 18, 103–115 (1999). https://doi.org/10.1038/sj.onc.1202269

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