Our long-term objective is to determine the mechanisms that regulate cellular growth and neoplastic transformation in breast tissue. Our current studies focus on how the tumor susceptibility gene 101 (TSG101) prevents tumorigenesis in mammary epithelial cells. TSG101 has been recently identified as an important factor for growth restriction and maintenance of genome stability in murine cell lines. The protein encoded by this gene has a very high similarity between human and rodents. Although chromosomal deletions of TSG 101 are rare events, aberrant transcripts are observed quite frequently in human cancers. Despite its important role for the maintenance of genome integrity in cultured cells, the biological function of TSG101 in vivo is largely unknown.
The specific aims of this proposal are to determine the role of TSG101 during normal development and tumorigenesis in vivo. We use genetically engineered mice that carry somatic mutation for TSG101 in mammary tissue. We will investigate whether TSG101 has characteristics of a tumor suppressor gene or mammary tissue. The critical domains within TSG101 that mediate its role during tumorigenesis will be determined by replacing the endogenous TSG1021 protein with shorter with shorter TSG101 mutants that lack specific parts of the protein. Finally, we will investigate the suggested role of TSG101 as a co-factor for the transcriptional repression of targeted by DNA methyltransferase 1. TSG101 might function in various different pathways that are important for growth, differentiation, and cancer progression. Thus, investigating the regulation of TSG101 expression and its biological function will provide us with new insights that will allow us to intercept oncogenic pathways, that require adequate levels of this protein to function normally.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Yassin, Rihab R,
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University of Nebraska Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhang, Qian; Sakamoto, Kazuhito; Wagner, Kay-Uwe (2014) D-type Cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells. Mol Cell Endocrinol 382:583-592
Sakamoto, Kazuhito; Schmidt, Jeffrey W; Wagner, Kay-Uwe (2012) Generation of a novel MMTV-tTA transgenic mouse strain for the targeted expression of genes in the embryonic and postnatal mammary gland. PLoS One 7:e43778
Morris, Chantey R; Stanton, Marissa J; Manthey, Karoline C et al. (2012) A knockout of the Tsg101 gene leads to decreased expression of ErbB receptor tyrosine kinases and induction of autophagy prior to cell death. PLoS One 7:e34308
Tu, Chun; Ahmad, Gulzar; Mohapatra, Bhopal et al. (2011) ESCRT proteins: Double-edged regulators of cellular signaling. Bioarchitecture 1:45-48
Zhang, Qian; Triplett, Aleata A; Harms, Don W et al. (2010) Temporally and spatially controlled expression of transgenes in embryonic and adult tissues. Transgenic Res 19:499-509
Tu, Chun; Ortega-Cava, Cesar F; Winograd, Paul et al. (2010) Endosomal-sorting complexes required for transport (ESCRT) pathway-dependent endosomal traffic regulates the localization of active Src at focal adhesions. Proc Natl Acad Sci U S A 107:16107-12
Oh, K B; Stanton, M J; West, W W et al. (2007) Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation. Oncogene 26:5950-9
Wagner, Kay-Uwe; Smith, Gilbert H (2005) Pregnancy and stem cell behavior. J Mammary Gland Biol Neoplasia 10:25-36
Triplett, Aleata A; Sakamoto, Kazuhito; Matulka, Laurice A et al. (2005) Expression of the whey acidic protein (Wap) is necessary for adequate nourishment of the offspring but not functional differentiation of mammary epithelial cells. Genesis 43:1-11
Krempler, Andrea; Qi, Yongyue; Triplett, Aleata A et al. (2004) Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 40:52-7

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