Studies of aberrations in mitogenic signaling pathway(s) in tumor cells may further our understanding of cancer and may identify novel therapeutic targets. We have recently identified and cloned the complete murine cDNA of Dab2, a 96 kd, mitogen-responsive phosphoprotein, which is one of the two identified mammalian homologs of the Drosophila protein Disabled (dDab). Structural features of Dab2 suggest a signaling role: Dab2 contains a non-SH2 phosphotyrosine interaction domain (PID or PTB) and proline-rich SH3 binding motifs. We have found that Dab2 associates with Grb2 in vivo and in vitro, and have formulated the hypothesis that Dab2 sequesters Grb2 from Sos and thus down-regulates Ras activity. In preliminary studies, we have found that Dab2 exhibited growth suppressing activity. Furthermore, using immunohistochemistry, we have shown that Dab2 is expressed mainly in epithelial/mesothelial cells of the ovarian surface epithelium. However, in a large percentage of epithelial ovarian tumors analyzed, Dab2 expression is lost in surface epithelial-derived tumor cells. Additionally, we have identified several putative dab2 genomic alterations in tumor cells and tissues, supporting the possibility that Dab2 functions as a negative growth regulator, and is inactivated in tumor cells. This study will investigate the role of Dab2 loss in breast and ovarian tumor development and examine the hypothesis that Dab2 is a tumor suppressor by two criteria: 1) the negative growth regulatory properties of Dab2, and 2) its altered expression, mutations, and deletions in tumors. The altered expression, mutations, and deletions of Dab2 will be investigated in breast and ovarian tumor tissues using approaches such as immunostaining, Western and Northern blotting, PCR amplification of genomic DNA, Southern blotting, RT-PCR and sequencing. Inducible and adenovirus-mediated expression of Dab2 will be used to reintroduce Dab2 expression into cancer cells lacking Dab2. Following restoration of Dab2 expression, the cells will be tested in tissue culture for growth, soft-agarose plates for colony formation, and nude mice for tumorigenicity. The results will clarify the role of Dab2 loss in the tumorigenicity of breast and ovarian cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079716-02
Application #
6124648
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Gallahan, Daniel L
Project Start
1998-12-10
Project End
2000-06-30
Budget Start
1999-12-01
Budget End
2000-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$174,146
Indirect Cost
Name
Emory University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Meng, Yue; Moore, Robert; Tao, Wensi et al. (2018) GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm. Dev Biol 436:55-65
Capo-Chichi, Callinice D; Cai, Kathy Q; Xu, Xiang-Xi (2018) Overexpression and cytoplasmic localization of caspase-6 is associated with lamin A degradation in set of ovarian cancers. Biomark Res 6:30
Smith, Elizabeth R; George, Sophia H; Kobetz, Erin et al. (2018) New biological research and understanding of Papanicolaou's test. Diagn Cytopathol 46:507-515
Smith, Elizabeth R; Meng, Yue; Moore, Robert et al. (2017) Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression. BMC Cell Biol 18:8
Capo-Chichi, Callinice D; Yeasky, Toni M; Smith, Elizabeth R et al. (2016) Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis. BMC Cell Biol 17:37
Tao, Wensi; Moore, Robert; Smith, Elizabeth R et al. (2016) Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice. Front Cell Dev Biol 4:129
Wang, Ying; Cai, Kathy Qi; Smith, Elizabeth R et al. (2016) Follicle Depletion Provides a Permissive Environment for Ovarian Carcinogenesis. Mol Cell Biol 36:2418-30
Tao, Wensi; Moore, Robert; Meng, Yue et al. (2016) Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol. J Lipid Res 57:809-17
Moore, Robert; Tao, Wensi; Meng, Yue et al. (2014) Cell adhesion and sorting in embryoid bodies derived from N- or E-cadherin deficient murine embryonic stem cells. Biol Open 3:121-8
Tao, Wensi; Moore, Robert; Smith, Elizabeth R et al. (2014) Hormonal induction and roles of Disabled-2 in lactation and involution. PLoS One 9:e110737

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