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Molecular and Cellular Biology, June 2005, p. 4625-4637, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4625-4637.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

YB-1 Is Important for Late-Stage Embryonic Development, Optimal Cellular Stress Responses, and the Prevention of Premature Senescence

Zhi Hong Lu, Jason T. Books, and Timothy J. Ley*

Division of Oncology, Departments of Medicine and of Genetics, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110

Received 17 December 2004/ Returned for modification 5 February 2005/ Accepted 25 February 2005

Proteins containing "cold shock" domains belong to the most evolutionarily conserved family of nucleic acid-binding proteins known among bacteria, plants, and animals. One of these proteins, YB-1, is widely expressed throughout development and has been implicated as a cell survival factor that regulates the transcription and/or translation of many cellular growth and death-related genes. For these reasons, YB-1 deficiency has been predicted to be incompatible with cell survival. However, the majority of YB-1–/– embryos develop normally up to embryonic day 13.5 (E13.5). After E13.5, YB-1–/– embryos exhibit severe growth retardation and progressive mortality, revealing a nonredundant role of YB-1 in late embryonic development. Fibroblasts derived from YB-1–/– embryos displayed a normal rate of protein synthesis and minimal alterations in the transcriptome and proteome but demonstrated reduced abilities to respond to oxidative, genotoxic, and oncogene-induced stresses. YB-1–/– cells under oxidative stress expressed high levels of the G1-specific CDK inhibitors p16Ink4a and p21Cip1 and senesced prematurely; this defect was corrected by knocking down CDK inhibitor levels with specific small interfering RNAs. These data suggest that YB-1 normally represses the transcription of CDK inhibitors, making it an important component of the cellular stress response signaling pathway.

* Corresponding author. Mailing address: Division of Oncology, Section of Stem Cell Biology, Campus Box 8007, 660 South Euclid Ave., St. Louis, MO 63110-1093. Phone: (314) 362-8831. Fax: (314) 362-9333. E-mail: tley{at}im.wustl.edu.

Molecular and Cellular Biology, June 2005, p. 4625-4637, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4625-4637.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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