Transcription factor family, nuclear factor κ-B (NFκβ) is involved in the initiation and progress of various cancers as well as in normal physiology. We are investigating the role of the NFκβ signaling pathway in ovarian function using transgenic mice. As part of this program, we have successfully bred mice with key pathway component, IKKβ, deleted (knocked-out) from granulosa cells; these mice cannot activate NFkB signaling. These studies will yield novel insights into ovarian function, indeed we have already used this transgenic mouse model to demonstrate a key role for NFkB signaling in ovulation.
Our studies in GCT cell lines indicated that the NFκβ signalling pathway is involved in the inhibition of apoptosis (cell death) in granulosa cells. We know little about this pathway which is generally regarded as being pro-proliferative and anti-apoptotic and are currently working to determine its precise role in the development of follicles in response to steroid hormones.
We will also include a histological analysis of the ovaries from the knockout mice and in vivo analyses exploring the ovarian response to stimuli. In addition, granulosa cells will be isolated and characterised in vitro. This model provides a powerful tool for not only understanding the functional role of NFkB signaling in the ovary but also for identifying the genes targeted by NFkB for regulation. We are also interested in exploring the consequences for estrogen receptor β (ERβ) given that NFkB signaling inhibits ERβ signaling in GCT.
Dr Simon Chu, MIMR-PHI Institute, OCRF L’Oreal Paris Research Fellow
Professor Christine Clarke, Westmead Hospital
Professor John Funder, MIMR-PHI Institute
Associate Professor Tim Cole, Biochemistry, Monash University
Professor Martin Matzuk, Baylor College of Medicine, USA
Professor Michael Karin, University of California, San Diego, USA
Jamieson, S. and Fuller, P.J.Characterization of the inhibitor of kappaB kinase (IKK) complex in granulosa cell tumors of the ovary and granulosa cell tumor-derived cell lines. Hormones and Cancer 4: 277-292, 2013.
Chu, S. Nishi, Y., Yanase, T., Nawata, H. and Fuller, P.J.Transrepression of estrogen receptor β signaling by nuclear factor-kB in ovarian granulosa cells. Molecular Endocrinology 18: 1919-1928, 2004.
Drummond, A.E. and Fuller, P.J.Activin and inhibin, estrogens and NFκB play roles in ovarian tumorigenesis. Is there crosstalk? Molecular and Cellular Endocrinology 359: 85-91, 2012.