Zhiyong Wang
I joined the Hunter Lab in September 2001 after I got a fellowship from California Breast Cancer Research Program (BCRP). I am having the best time of my career here in the lab. It is a great lab.
My research is about in vivo roles of p160 transcriptional coactivators in mice. The p160 family has three members: p/CIP/AIB1, SRC-1/NcoA1, and TIF-2/Grip1. They were initially identified as cofactors that enhance transcriptional activities of nuclear hormone receptors (they are hormone-dependent transcription factors). One of the members, p/CIP/AIB1, was independently discovered as a gene amplified and overexpressed in breast and ovarian cancers. It functions as a coactivator for estrogen receptor (ER), which is important for proliferation of ER positive breast cancer cells.
The p160 family members have been implicated in other signaling pathways including NF-kappa B, STATs, and AP1 by in vitro experiments. Whether these proteins play relevant roles in vivo is unclear. I decided to use transgenic and knockout approaches to investigate the question in mice. I have generated p/CIP single null mutant mice. They are healthy and fertile. One phenotype I have noticed is that the knockout mice are 30-50% smaller than their sex-matched littermates. Deficiency of IGF-1 level and IGF1 signaling might account for the somatic growth defect. Mammary gland of these p/CIP null mice is normal during different stages of development. I have also generated SRC-1 and p/CIP double knockout mice with collaboration of Drs Qao Qi and Johnardan Reddy of Northwestern University.
More than 70% of the double null mutant mice die before they are three weeks old, indicating a gene-dosage effect of p/CIP and SRC-1 for mouse survival. I am now studying development of different organs in the double knockout mice. To me, it is exciting time to get closer to understand in vivo roles of these coactivators. Preliminary results seem to suggest that some pathways such as NF-kappa B and STAT1 function normally in the double null mice. There are also evidences to suggest specific pathways dependent on these coactivators. I am planning to use cells and tissues from the knockout mice to define the pathways involved and study underlying mechanisms for the developmental defects in the knockout mice,