The goal of this project is to understand how (B-Ras1 and (B-Ras2, members of an unusual sub-class of Ras-like proteins, are regulated, and how they in turn regulate pathways leading to NF-(B and Ral GTPases. These proteins were originally discovered through their physical interaction with the I(B( protein, and in vitro and overexpression experiments indicated that they are inhibitors of NF-(B. However the true physiological role of these proteins has remained unclear. Our preliminary results using knock-outs of both (B-ras genes shows that they act to inhibit both NF-(B and Ral GTPase pathways. Interestingly, mice lacking (B-Ras proteins also die perinatally due to defects in lung development. In this research proposal we aim to ask the following questions.
In Aim 1 we will study how (B-Ras actually regulates NF-(B. While affecting the stability of I(B( is a likely mechanism, many questions about exactly how (B-Ras functions remains unanswered. Availability of cells lacking (B-Ras will allow us to explore the underlying mechanism in a systematic manner. We will also use mice lacking (B-Ras in macrophages to study mouse models of inflammation including septic shock and collagen-induced arthritis.
In Aim 2 we will ask how (B-Ras regulates Ral, and determine whether activated Ral contributes to NF-(B activation. We will study the mechanism by which growth factor signaling disrupts the (B-Ras-RalGAP complex, and determine why binding to (B-Ras inhibits the activity of RalGAP. We will also test whether the activated Ral in (B-Ras deficient cells contributes to NF-(B activation. Finally in Aim 3 we will explore the lung phenotype seen in the (B-Ras-deficient animals. We will study the mechanism of dysregulated surfactant expression, in particular the role of NF-(B in the process. In summary these studies will provide significant new insight into the biology of these evolutionarily conserved, yet enigmatic, members of this Ras-like family of proteins.
Chronic inflammation underlies many diseases such as arthritis, asthma and cancer. The transcription factor NF-(B plays a key role in regulating inflammation and understanding the molecular mechanism that regulates NF-(B is of great interest. In this proposal we will determine how (B-ras proteins regulate the activity of NF-(B and Ral GTPases, and determine why lack of (B-Ras leads to defects in lung development.
| Castellanos-Rubio, Ainara; Fernandez-Jimenez, Nora; Kratchmarov, Radomir et al. (2016) A long noncoding RNA associated with susceptibility to celiac disease. Science 352:91-5 |
| Postler, Thomas S; Ghosh, Sankar (2015) Bridging the Gap: A Regulator of NF-?B Linking Inflammation and Cancer. J Oral Biosci 57:143-147 |
| Oeckinghaus, Andrea; Postler, Thomas S; Rao, Ping et al. (2014) ?B-Ras proteins regulate both NF-?B-dependent inflammation and Ral-dependent proliferation. Cell Rep 8:1793-1807 |
| Hayden, Matthew S; Ghosh, Sankar (2014) Regulation of NF-?B by TNF family cytokines. Semin Immunol 26:253-66 |
| Hayden, Matthew S; Ghosh, Sankar (2012) NF-?B, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203-34 |
| Ghosh, Sankar; Hayden, Matthew S (2012) Celebrating 25 years of NF-?B research. Immunol Rev 246:5-13 |
| Klein, Ulf; Ghosh, Sankar (2011) The Two Faces of NF-?B Signaling in Cancer Development and Therapy. Cancer Cell 20:556-8 |
| Oeckinghaus, Andrea; Ghosh, Sankar (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1:a000034 |
