Disabled-2 (Dab2) is an SH3 domain-binding partner of Grb2. Xu XX 1998 et al.
Disabled-2 (Dab2), a mammalian structural homolog of Drosophila Disabled (Dab), is a mitogen-responsive phosphoprotein. It has been speculated to be a negative regulator of growth since its expression is lost in ovarian carcinomas. Dab2 contains a C-terminal proline-rich domain with sequences similar to those found in Sos, a guanine nucleotide exchange factor for Ras. The proline-rich sequences of Sos mediate the interaction of Sos with Grb2, an adaptor protein which coupled tyrosine kinase receptors to Sos. Herein, we have investigated the possibility that Dab2 interacts with Grb2. In experiments of co-immunoprecipitation from BAC1.2F5 macrophage cell lysates, significant quantities of Grb2 were associated with both Sos and Dab2, although Dab2 and Sos were not present in the same complex. Transfection of Dab2 into a Dab2-negative cell line (293 cells) decreased the amount of Grb2 associated with Sos, suggesting that Dab2 competes with Sos for binding to Grb2. Proline-rich peptides corresponding to Dab2 (#661-669) and to Sos (#1146-1161) inhibited the binding of Dab2 to Grb2, but were less effective in disrupting the Grb2-Sos complex. The expressed proline-rich domain of Dab2 (#600-730) bound Grb2, but other regions of Dab2 failed to bind Grb2. Both of the individual SH3 domains of Grb2 bound to Sos (N-terminal SH3 domain > C-terminal SH3 domain), but binding to Dab2 required the intact Grb2, suggesting cooperative binding using both SH3 domains of Grb2. These data indicate that Dab2 binds to the SH3 domains of Grb2 via its C-terminal proline-rich sequences. Dab2 may modulate growth factor/Ras pathways by competing with Sos for binding to Grb2.
/////////////////////////
A DNA-fingerprinting approach has been adapted to detect differentially expressed genes in human ovarian carcinoma Mok et al. (1994) .
This method is based on the use of arbitrary primers to generate fingerprints from total RNA isolated from normal
ovarian epithelial cells and ovarian carcinoma cells by polymerase chain reaction (PCR). Using this method,
two cDNA fragments (DOC-1 and DOC-2) were cloned which were present in normal ovarian surface epithelial cells but
consistently absent in all of the ovarian cancer cell lines from the differential display. The differential expression of the genes in the tumor cell lines as well as in the
tumor tissues was also confirmed by Northern analysis. The clone DOC-2, which is a 800-bp cDNA fragment, has one
open reading frame suggesting that the gene may be translated. The antisense DOC-2 riboprobe
revealed a hybridization signal which was restricted to the human surface ovarian epithelium.
NCBI Summary:
DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines. The 770-amino acid predicted protein has an overall 83% identity with the mouse p96 protein, a putative mitogen-responsive phosphoprotein; homology is strongest in the amino-terminal end of the protein in a region corresponding to the phosphotyrosine interaction domain. The down-regulation of DAB2 may play an important role in ovarian carcinogenesis. This gene was initially named DOC2 (for Differentially expressed in Ovarian Cancer) and is distinct from the DOC2A and DOC2B genes (for double C2-like domains, alpha and beta).
General function
Intracellular signaling cascade
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Tumorigenesis
Comment
Expression regulated by
Comment
Ovarian localization
Granulosa, Surface epithelium
Comment
Changes in granulosa cells gene expression associated with growth, plateau and atretic phases in medium bovine follicles. Douville G 2014 et al.
BACKGROUND
The objective of this study was to build the transcriptomic profile of granulosa cells originating from follicles 6 to 9?mm in diameter in dairy cattle using microarrays.
METHODS
GRANULOSA CELLS ORIGINATING FROM THREE DIFFERENT PHASES OF ANTRAL FOLLICLE GROWTH WERE COMPARED: growing (G), plateau (P) and atresia (A), as categorized by flow cytometry profiles of DNA. The growing and atretic conditions were each hybridized against the plateau condition as a reference in order to understand the specific biological mechanisms modulated in this class of follicles.
RESULTS
2,942 genes were differentially expressed in P vs. G and 1,974 in A vs. P. A clear segregation of the 3 phases was confirmed by between group analysis (BGA). The first characteristic of the plateau phase is the activation of the upstream regulators TP53 and PTEN which participate in the reduction of cell growth through MYC, FOS and E2F1-2-3. We also observed the down-regulation of steroidogenesis genes: CYP11A1 and CYP19A1, in the granulosa cells of the plateau phase relative to the growth phase. On the other hand, the A vs. P contrast showed up-regulation of multiple transcripts associated to apoptosis: CCT2, DAB2, DSG2 and TGM2.
CONCLUSIONS
This study offers multiple candidate genes to be further studied in order to elucidate their role in the modulation of follicular development and, ultimately, of oocyte quality.
/////////////////////////