Phosphoinositide lipids (PIPs) drive cancer by functioning as interaction surfaces for oncogenic proteins at cytoplasmic membranes. However PIPs in the nucleus exist outside membranes, bound to unidentified nuclear proteins. Over 40% of nuclear PI(4,5)-bisphosphate (PIP2) and 80% of nuclear PI(3,4,5)-triphosphate (PIP3) exists in this non-membrane state, yet the function of nuclear PIPs is almost totally unexplored. Similarly, the lipid signaling enzymes that remodel PIPs shuttle into the nucleus, but their enzymatic functions in the nucleus are all but unknown. Without understanding nuclear PIP function, a huge hole exists in the complete picture of how these signaling lipids promote oncogenesis.
We established in human cell lines that nuclear PIPs are bound by the NR5A nuclear receptors (NR5A1 & NR5A2). NR5As bind DNA to regulate the expression of steroid & cholesterol homeostatic genes in the liver & adrenals. PIP3 activates, while PIP2 inhibits NR5As. We also discovered that the lipid phosphatase PTEN tumor suppressor and a little known PIP2-kinase called “Inositol Polyphosphate Multi-Kinase” (IPMK) use their enzyme activities to remodel PIPs bound to NR5As10. These enzymes also physically interact with NR5As. Altogether, we have shown that IPMK & PTEN functionally and directly interact with NR5As, remodeling nuclear PIP3 bound to NR5As.
The hypothesis tested here is that PTEN is a chromatin-bound regulatory enzyme, remodeling PIP3 associated with chromatin to control gene expression. The nuclear activity of PTEN is decoupled from p110 PI3-kinases, thus our mechanism provides a new reason why some patients with PTEN-negative tumors are resistant to PI3K inhibitors.
Gregory A. Sowd, PhD. - Postdoctoral Fellow
Nuclear lipid genomics in PTEN negative cancers.
Hometown - North Canton, OH
B.S. Biochemistry Virginia Tech Blacksburg, VA
Specialist Environmental Health University of Pittsburgh, PA (Patricia Opresko)
Ph.D. Biological Sciences Vanderbilt University (Ellen Fanning)
See Greg's Publications on PubMed