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Molecular and Cellular Biology, September 2001, p. 5925-5934, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5925-5934.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Induction of Cyclin D1 Transcription and CDK2 Activity by Notchic: Implication for Cell Cycle Disruption in Transformation by Notchic

Chiara Ronchini and Anthony J. Capobianco*

Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267-0524

Received 28 February 2001/Returned for modification 26 April 2001/Accepted 8 June 2001

Notch genes encode a family of transmembrane proteins that are involved in many cellular processes such as differentiation, proliferation, and apoptosis. Although it is well established that all four Notch genes can act as oncogenes, the mechanism by which Notch proteins transform cells remains unknown. Previously, we have shown that transformation of RKE cells can be conditionally induced by hormone activation of Notchic-estrogen receptor (ER) chimeras. Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics. Transcriptional activation of cyclin D1 is independent from serum-derived growth factors and de novo synthesis of secondary transcriptional activators. Moreover, hormone activation of Notchic-ER proteins induces CDK2 activity in the absence of serum. Upregulation of cyclin D1 and activation of CDK2 by Notchic result in the promotion of S-phase entry. These data demonstrate the first evidence that Notchic proteins can directly regulate factors involved in cell cycle control and affect cellular proliferation. Furthermore, nontransforming Notchic proteins do not induce cyclin D1 expression, indicating that the mechanism of transformation involves cell cycle deregulation through constitutive expression of cyclin D1. Finally, we have identified a CSL [stands for CBF1, Su(H), and Lag-1] binding site within the human and rat cyclin D1 promoters, suggesting that Notchic proteins activate cyclin D1 transcription through a CSL-dependent pathway.

* Corresponding author. Mailing address: Department of Molecular Genetics, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524. Phone: (513) 558-3664. Fax: (513) 558-8474. E-mail: tony.capobianco{at}uc.edu.

Molecular and Cellular Biology, September 2001, p. 5925-5934, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5925-5934.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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