STEPHEN F. KONIECZNY
Professor and Interim Head, Department of Biological Sciences
Transcriptional gene regulation in eukaryotic cells
The research in our laboratory involves defining the molecular mechanisms that regulate gene expression in pancreatic epithelial cells during development and in cases of pancreas disease, including pancreatitis and pancreatic cancer. The goal of our studies is to identify the earliest transcriptional changes that are induced upon disease initiation and to determine mechanisms of harnessing downstream pathways to prevent and/or treat advanced stage disease. We have focused our studies on two different transcription factor families - the basic helix-loop-helix (bHLH) factors and the SRY-related HMG-box family of SOX proteins since both bHLH and SOX members are essential to controlling developmental and cell proliferation events. Indeed, alterations in bHLH and SOX factor activity, or in gene expression patterns, often correlate with the development of pancreatic disease including pancreatic cancer.
We have identified the novel bHLH factor, MIST1, as critical to the developing and adult pancreatic tissue. Mist1 gene expression is restricted to the exocrine gland portion of the pancreas, which is the area from which most pancreatic tumors are derived. It is this adult expression pattern that we are particularly interested in exploiting since the Mist1 gene becomes rapidly silenced in diseased tissue. In order to understand the role of MIST1 in the development and function of the exocrine pancreas we have generated several Mist1 mouse models where we can conditionally delete the Mist1 gene or can artificially turn on Mist1 expression. We have found that secretory cells of Mist1KO mice exhibit a highly disorganized cell structure that makes the cells more prone to developing into a pancreatic tumor. Functional studies, coupled with gene array and RNA-Seq analyses, have revealed that Mist1KO mice no longer express the gap junction protein connexin 32 and that loss of Cx32 leads to cells that fail to communicate. Importantly, induced expression of MIST1 in damaged cells reverts the damaged state and restores normal gene expression patterns, even in the adult mouse. Future studies are aimed at identifying additional Mist1 targets in the hope of understanding how this key transcription factor functions during development.
Pancreatic cancer mouse models
One goal of our laboratory is to generate transgenic mouse tumor models were we can study the early events associated with pancreatic cancer. In this regard, we have focused on the transcription factors MIST1 and SOX9 since these exhibit different expression patterns in healthy and diseased tissue. For instance, MIST1 expression is normally restricted to pancreatic acinar cells whereas SOX9 is found exclusively in duct cells. However, when oncogenic Kras is expressed in acinar cells, the Mist1 gene is rapidly silenced while the Sox9 gene is activated in this cell type. Interestingly, expression of Kras in a Mist1KO background greatly accelerates pancreatic tumor formation whereas activation of Kras in a Sox9KO background completely prevents tumor formation. These findings suggest that MIST1 is needed to prevent pancreatic cancer development whereas SOX9 is essential to tumor formation. Using a variety of genetically engineered mouse models as well as in vitro strategies using shRNA, we are dissecting the pathways that are controlled by the MIST1 and SOX9 networks. Additionally, we are taking a genomics approach of identifying downstream gene targets of MIST1 and SOX9 to decipher their importance to pancreatic disease initiation. Our long-term goals are to exploit these transcription networks to develop more effective therapeutic strategies to help patients suffering from pancreatic disease.
B.S., University Massachusetts, Amherst, 1977
Ph.D., Brown, 1982
- Leadership Award, Department of Biological Sciences - 2016
- Favorite Faculty Nominee - 2016
- Fellow, AAAS (American Association for the Advancement of Science) - 2014
- Purdue College of Science Graduate Student Mentoring Award - 2014
- J. Alfred and Martha Chiscon Award for Outstanding Undergraduate Teaching - 2014
- Inductee in Purdue University's "Book of Great Teachers" - 2008
- Inducted into Purdue's Teaching Academy - 2005
- Charles B. Murphy Award for Outstanding Undergraduate Teaching - 2004
- Seed for Success Award - 2004, 2005, 2008, 2010, 2013, 2014
NIH R01 DK55489-18 "Pancreas Transcription Factors and Disease Model Systems".
NIH R01 CA124586-09 "Kras-Induced Cellular Plasticity in Pancreatic Cancer".
NIH 5P30CA023168-35 "Transgenic Mouse Development".
American Society for Cell Biology
American Society for Microbiology
Sigma Xi Scientific Research Society
Society for Developmental Biology
American Pancreas Association
Professional Faculty Research
(Eukaryotic molecular biology) Gene expression during mammalian development; cancer model systems.