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Molecular and Cellular Biology, September 1999, p. 5913-5922, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Myc Downregulation by Transforming Growth Factor beta  Required for Activation of the p15Ink4b G1 Arrest Pathway

Beverley J. Warner, Stacy W. Blain, Joan Seoane, and Joan Massagué*

Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Received 17 March 1999/Returned for modification 15 April 1999/Accepted 28 May 1999

The antimitogenic action of transforming growth factor beta  (TGF-beta ) in epithelial cells involves cyclin-dependent kinase (cdk) inhibitory gene responses and downregulation of c-Myc expression. Although the cdk inhibitory responses are sufficient for G1 arrest, enforced expression of c-Myc prevents G1 arrest by TGF-beta . We investigated the basis of this antagonism by using Mv1Lu lung epithelial cell lines that conditionally express levels of human c-Myc. We show that c-Myc prevents induction of the cdk4 inhibitor p15Ink4b and the subsequent inhibition of G1 cdks by TGF-beta . We assessed the significance of this effect by analyzing the oligomeric state of cdk4 in these cells. In proliferating cells, endogenous cdk4 is distributed among three populations: an abundant high-molecular-mass (>400-kDa) pool of latent cdk4 that serves as a source of cdk4 for cyclin D, a low-abundance pool containing active cyclin D-cdk4 complexes, and an inactive population of monomeric cdk4. Cell stimulation with TGF-beta converts the latent and active cdk4 pools into inactive cdk4, an effect that is specifically mimicked by overexpression of p15 but not by other forms of G1 arrest. This process of TGF-beta -induced cdk4 inactivation is completely blocked by expression of c-Myc, even though the latent and active cdk4 complexes from c-Myc-expressing cells remain sensitive to dissociation by p15 in vitro. c-Myc causes a small increase in cyclin D levels, but this effect contributes little to the loss of TGF-beta responses in these cells. The evidence suggests that c-Myc interferes with TGF-beta activation of the p15 G1 arrest pathway. TGF-beta must therefore downregulate c-Myc in order to activate this pathway.

* Corresponding author. Mailing address: Box 116, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-8975. Fax: (212) 717-3298. E-mail: j-massague{at}ski.mskcc.org.

Molecular and Cellular Biology, September 1999, p. 5913-5922, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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