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Translational Deregulation in PDK-1^–/– Embryonic Stem Cells

Yuichi Tominaga, 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 p70^S6K, 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.

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

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

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