The function of every tissue in the body is controlled by hormones and growth factors that trigger the receptors proteins and switch on or off specific gene networks.
One group of receptors called nuclear receptors play a vast array of roles starting with the maintenance of stem cells in the embryo to reproduction, metabolism and numerous physiological responses. While all cells contain an identical repertoire of approximately 30,000 genes they are not all expressed and each type of cell expresses distinct gene networks that determine the function of each type of cell.
Nuclear receptors regulate gene activity by recruiting cofactor proteins by recognising specific genes and then either switching them on or off. The Parker laboratory have focussed on two types of cofactor protein, RIP140 that they discovered in breast cancer cells and a coactivator family called NCoA, These cofactors are widely expressed but have very specific roles including essential functions in the ovary, breast and in embryonic stem cells.
RIP140 is essential for female fertility, specifically ovulation. It promotes the signal that prepares cumulus cells surrounding the oocyte or egg for expansion prior to ovulation. Remarkably the same signal is required for mammary gland development and accordingly we have found that RIP140 is essential for the formation of ducts in the breast during development. We are now examining its role in breast cancer. RIP140 is also crucial for determining the amount of fat we store in adipose tissues. It prevents the burning of fat depots and its absence leads to a lean appearance. The manipulation of RIP140 expression or activity may offer a therapeutic means for reducing obesity and consequently the incidence of type 2 diabetes.
NCoA3 was initially discovered because it is over expressed in breast cancer but it has a number of functions in normal cells. We have found that it plays a role in the embryo to maintain the renewal of stem cells prior to their differentiation into different cell lineages. One of the most exciting recent developments in the stem cell field is the discovery that it is possible to convert adult cells into embryonic stem cells by expressing four specific transcription factors. The ability to do this will provide cell systems that can provide a disease model for future studies. We have found that NCoA3 is a cofactor for a nuclear receptor that not only maintains stem cells in the embryo but is also required to reprogram adult cells into stem cells.
Our goals are to determine the (1) function of RIP140 in ovulation and in mammary gland development and breast cancer, (2) mechanism of action of NCoA3 in stem cells.