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Molecular and Cellular Biology, January 2003, p. 150-162, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.150-162.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Tsg101 Is Essential for Cell Growth, Proliferation, and Cell Survival of Embryonic and Adult Tissues

Kay-Uwe Wagner,1* Andrea Krempler,1 Yongyue Qi,1 KyungRan Park,1 MaLinda D. Henry,1 Aleata A. Triplett,1 Gregory Riedlinger,2 Edmund B. Rucker III,2,1 and Lothar Hennighausen2

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805,1 Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-08222

Received 31 July 2002/ Returned for modification 9 September 2002/ Accepted 25 September 2002

Tumor susceptibility gene 101 (Tsg101) was identified in a random mutagenesis screen for potential tumor suppressors in NIH 3T3 cells. Altered transcripts of this gene have been detected in sporadic breast cancers and many other human malignancies. However, the involvement of this gene in neoplastic transformation and tumorigenesis is still elusive. Using gene targeting, we generated genetically engineered mice with a floxed allele of Tsg101. We investigated essential functions of this gene in vivo and examined whether the loss of function of Tsg101 results in tumorigenesis. Conventional knockout mice were generated through Cre-mediated excision of the first coding exon in the germ line of mouse mammary tumor virus (MMTV)-Cre transgenic mice. The complete ablation of Tsg101 in the developing embryo resulted in death around implantation. In contrast, mammary gland-specific knockout mice developed normally but were unable to nurse their young as a result of impaired mammogenesis during late pregnancy. Neither heterozygous null mutants nor somatic knockout mice developed mammary tumors after a latency of 2 years. The Cre-mediated deletion of Tsg101 in primary cells demonstrated that this gene is essential for the growth, proliferation, and survival of mammary epithelial cells. In summary, our results suggest that Tsg101 is required for normal cell function of embryonic and adult tissues but that this gene is not a tumor suppressor for sporadic forms of breast cancer.

* Corresponding author. Mailing address: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Rm. 8009, Omaha, NE 68198-6805. Phone: (402) 559-3288. Fax: (402) 559-4651. E-mail: kuwagner{at}unmc.edu.

{dagger} Present address: Animal Science Research Center, University of Missouri, Columbia, MO 65211.

Molecular and Cellular Biology, January 2003, p. 150-162, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.150-162.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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