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Molecular and Cellular Biology, November 2000, p. 8420-8431, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

p53 Binds Selectively to the 5' Untranslated Region of cdk4, an RNA Element Necessary and Sufficient for Transforming Growth Factor beta - and p53-Mediated Translational Inhibition of cdk4

Susan J. Miller,1,dagger Tuangporn Suthiphongchai,1,Dagger Gerard P. Zambetti,2 and Mark E. Ewen1,*

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115,1 and Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 381052

Received 15 June 2000/Returned for modification 22 August 2000/Accepted 1 September 2000

One consequence of transforming growth factor beta  (TGF-beta ) treatment is inhibition of Cdk4 synthesis, and this is dependent on p53. Here, we show that the 5' untranslated region (UTR) of the cdk4 mRNA is both necessary and sufficient for wild-type p53-dependent TGF-beta -regulated translational inhibition of cdk4. Wild-type p53 bound selectively to the 5' UTR of the cdk4 mRNA and inhibited translation of RNAs that contain this region. RNA binding and translational control are two genetically separable functions of p53, as are specific and nonspecific RNA binding. Moreover, transactivation-defective mutants of p53 retain the ability to regulate cdk4 translation. Our findings suggest that p53 functions as a regulator of translation in response to TGF-beta in vivo.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney St., Boston, MA 02115. Phone: (617) 632-2206. Fax: (617) 632-5417. E-mail: mark_ewen{at}dfci.harvard.edu.

dagger Present address: Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215.

Dagger Present address: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.

Molecular and Cellular Biology, November 2000, p. 8420-8431, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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