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Molecular and Cellular Biology, December 2006, p. 9279-9290, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00724-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Nucleostemin Delays Cellular Senescence and Negatively Regulates TRF1 Protein Stability{triangledown} ,{dagger}

Qubo Zhu, Hiroaki Yasumoto, and Robert Y. L. Tsai*

Center for Cancer and Stem Cell Biology, Alkek Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030

Received 26 April 2006/ Returned for modification 18 June 2006/ Accepted 15 September 2006

Nucleostemin (NS) encodes a nucleolar GTP-binding protein highly enriched in the stem cells and cancer cells. To determine its biological activity in vivo, we generated NS loss- and gain-of-function mouse models. The embryogenesis of homozygous NS-null (NS–/–) mice was aborted before the blastula stage. Although the growth and fertility of heterozygous NS-null (NS+/–) mice appeared normal, NS+/– mouse embryonic fibroblasts (MEFs) had fewer NS proteins, a lower population growth rate, and higher percentages of senescent cells from passage 5 (P5) to P7 than their wild-type littermates. Conversely, transgenic overexpression of NS could rescue the NS–/– embryo in a dose-dependent manner, increase the population growth rate, and reduce the senescent percentage of MEFs. Cell cycle analyses revealed increased pre-G1 percentages in the late-passage NS+/– MEF cultures compared to the wild-type cultures. We demonstrated that NS could interact with telomeric repeat-binding factor 1 (TRF1) and enhance the degradation but not the ubiquitination of the TRF1 protein, which negatively regulates telomere length and is essential for early embryogenesis. This work demonstrates the roles of NS in establishing early embryogenesis and delaying cellular senescence of MEFs and reveals a mechanism of a NS-regulated degradation of TRF1.

* Corresponding author. Mailing address: 2121 W. Holcombe Blvd., Houston, TX 77030. Phone: (713) 677-7690. Fax: (713) 677-7512. E-mail: rtsai{at}ibt.tamhsc.edu.

{triangledown} Published ahead of print on 25 September 2006.

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

Molecular and Cellular Biology, December 2006, p. 9279-9290, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00724-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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