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.
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.
Miller
S J
SJ
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Suthiphongchai
T
T
Zambetti
G P
GP
Ewen
M E
ME
D020121:5' Untranslated Regions; D000818:Animals; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D009154:Mutation; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins; D022661:RNA, Untranslated / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D020121:5' Untranslated Regions; D011518:Proto-Oncogene Proteins; D022661:RNA, Untranslated; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases