professor & associate director, Eppley Institute and Eppley Cancer Center
Identification and exploitation of new molecular targets in cancer.
Summary of Research
The Brattain Laboratory is focused on the identification and exploitation of novel molecular targets in cancer. There are two major areas of investigation that are ongoing in the laboratory. One involves a group of molecules called receptor tyrosine kinases (RTK’s) and signal transduction while the other deals with control of gene expression in cancer by HDAC enzymes that remodel chromatin and their inhibition of tumor suppressor activity by TGFϐ
We are using shRNA approaches to stably knockdown novel RTK’s and signaling targets to determine effects on tumor formation and growth in vivo and to determine molecular mechanisms underlying these effects in vitro. For example, we have developed orthotopic athymic mouse models of human colon cancer that metastasize to the liver and lung similarly to human disease. We have found that an RTK of the MET family, RON K, plays an essential role in the metastatic process through inhibition of orthotopic transplants of stable shRNA transfectants of colon cancer cells bearing this receptor. Using similar approaches in vitro we have now learned that this receptor activates a gain of function PI3 kinase (PI3K) mutant that is essential to aberrant cell survival signaling during the metastatic process. We are now pursuing the function of a signaling intermediate of a recently identified link in the PI3K/AKT pathway designated ARK.
We have had a long standing interest in the mechanisms which lead to epigenetic repression of the TGFϐ type I and type II receptors in cancer as both of these are required for the signaling of this tumor suppressor and are frequently lost in a variety of cancers. Not surprisingly, the Sp1 family is an important determinant of transcription in these TATA- less genes. Using siRNA approaches and ChIP techniques we found that both receptor genes are silenced by recruitment of HDAC1 to an Sp1/p300 complex. HDAC1 knockdown by siRNA results in re-expression of the receptors with re-establishment of TGFϐ tumor suppressor activity. One of the outcomes of TGFϐ tumor suppressor activity is the induction of apoptosis. We have found that the mechanism by which this apoptosis is driven is through the transcriptional repression of transcription of the IAP protein family member survivin. We are currently determining the transcriptional mechanism associated with repression of survivin.
Tel: 402-559-4902 (Office)
E-mail: Michael Brattain