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Molecular and Cellular Biology, October 2005, p. 8465-8475, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8465-8475.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Translational Deregulation in PDK-1–/– Embryonic Stem Cells{dagger}

Yuichi Tominaga,{ddagger} Tanja Tamgüney, Marina Kolesnichenko, Benoit Bilanges, and David Stokoe*

Cancer Research Institute, University of California, San Francisco, San Francisco, California 94115

Received 4 October 2004/ Returned for modification 15 November 2004/ Accepted 5 July 2005

PDK-1 is a protein kinase that is critical for the activation of many downstream protein kinases in the AGC superfamily, through phosphorylation of the activation loop site on these substrates. Cells lacking PDK-1 show decreased activity of these protein kinases, including protein kinase B (PKB) and p70S6K, whereas mTOR activity remains largely unaffected. Here we show, by assessing both association of cellular RNAs with polysomes and by metabolic labeling, that PDK-1–/– embryonic stem (ES) cells exhibit defects in mRNA translation. We identify which mRNAs are most dramatically translationally regulated in cells lacking PDK-1 expression by performing microarray analysis of total and polysomal RNA in these cells. In addition to the decreased translation of many RNAs, a smaller number of RNAs show increased association with polyribosomes in PDK-1–/– ES cells relative to PDK-1+/+ ES cells. We show that PKB activity is a critical downstream component of PDK-1 in mediating translation of cystatin C, RANKL, and Rab11a, whereas mTOR activity is less important for effective translation of these targets.

* Corresponding author. Mailing address: Cancer Research Institute, University of California, 2340 Sutter St. N319, San Francisco, CA 94115. Phone: (415) 502-2958. Fax: (415) 502-3179. E-mail: stokoe{at}cc.ucsf.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Discovery Research Laboratory, Tokyo R&D Center, Daiichi Pharmaceuticals, 1-16-13 Kita-kasai, Edogawa-ku, Tokyo 134-8630, Japan.

Molecular and Cellular Biology, October 2005, p. 8465-8475, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8465-8475.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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