Interdisciplinary Life Science - PULSe Great research is a matter of choice

Stephen F. Konieczny

Stephen F. Konieczny Profile Picture

Professor of Biological Sciences
Ph.D. - 1982 - Brown University


Contact Info:

konieczs@purdue.edu
765-494-7976


Training Group(s):
Molecular Signaling and Cancer Biology
Chromatin and Regulation of Gene Expression


Current Research Interests:

Overview: Our laboratory is defining the molecular mechanisms by which basic helix-loop-helix (bHLH) transcription factors regulate gene expression in pancreatic and mammary gland epithelial cells during development and in cases of tumor initiation and progression. Alterations in bHLH factor activity, or in bHLH gene expression patterns, often correlate with the development of pancreatic and breast cell tumors.

Pancreas development: We have identified a novel bHLH factor, Mist1, that is expressed in developing and adult pancreatic tissues. Mist1 gene expression is restricted to the exocrine portion of the pancreas, which is the area from which most pancreatic tumors are derived. In order to understand the role of Mist1 in the development and function of these cell types we have generated Mist1 null (Mist1KO) mice in which the Mist1 gene has been deleted. Functional studies, coupled with gene array analysis, have revealed that Mist1KO mice no longer express several genes involved in growth regulation. Future studies are aimed at identifying additional Mist1 target genes to understand how this key transcription factor functions during development.

Pancreatic cancer mouse models: One goal of our laboratory is to generate novel transgenic mouse tumor models. We are using these models to study a variety of cancers so that new therapeutic strategies can be developed that will inhibit tumor formation and metastasis. One mouse model that we generated contains a mutated Kras oncogene (KrasG12D) positioned into the Mist1 locus. As expected, these mice develop pancreatic cancers that metastasize. Interestingly, the pancreatic tumor phenotype is greatly enhanced when the Mist1-KRas mice are crossed to the Mist1KO mice. These results suggest that Mist1 can function as a tumor suppressor gene. We also have generated additional mouse lines that utilize a tissue-specific Cre-inducible strategy to position oncogenes and tumor suppressor genes within a common cancer signaling pathway to understand the initiation events and progression pathways that are instrumental in generating pancreatic cancer. Using these mice and lineage tracing strategies we have identified the initiator cell that gives rise to pancreatic cancer in these animal models. We are currently assessing these pathways in the human population to determine if similar pathways are instrumental in clinical pancreatic cancer settings.

Mammary gland development and breast cancer: Our laboratory is also interested in understanding the molecular and genetic events that control cellular specificity, differentiation and growth control of mammary epithelial cells. We have shown that the bHLH factor Mist1 is expressed exclusively in quiescent mammary gland cells and not in breast tumor cells. Forced Mist1 expression in tumor cells results in cessation of cellular proliferation. We are generating Mist1-Cre mouse lines that will be used to activate specific breast tumor promotion genes to determine how Mist1 regulates mammary epithelial transformation events.



Selected Publications:

Tuveson, D.A., Zhu*, L., Gopinathan, A., Willis, N.A., Kachatrian, L., Grochow, R., Pin, C.L., Mitin, N.Y., Taparowsky, E.J., Gimotty, P.A., Hruban, R.H., Jacks, T. and Konieczny, S.F. (2006) Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma. Cancer Research 66: 242-247.

Mitin, N., Konieczny, S.F. and Taparowsky, E.T. (2006) Ras and the RAIN/RasIP1 effector. In Methods of Enzymology, 407: 322-335.

Konieczny, S.F. Mist1. AfCS-Nature Molecule Pages (2006) (doi:10.1038/mp.a003676.01).

Zhao, Y., Johansson*, C., Tran*, T., Bettencourt, R., Itahana, Y., Desprez, P.-Y. and Konieczny, S.F. (2006) Identification of a bHLH transcription factor expressed in mammary gland alveolar cells and required for maintenance of the differentiated state. Mol. Endocrinology 20: 2187-2198.

Ramsey, V.G., Doherty, J.M., Chen, C.C., Stappenbeck, T.S., Konieczny, S.F. and Mills, J.C. (2007) The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires Mist1. Development 134: 211-222.

Tran, T., Jia, D., Sun, Y. and Konieczny, S.F. (2007) The bHLH domain of Mist1 is sufficient to activate gene transcription. Gene Expression 13: 241-253.

Zhu, L., Shi, G., Schmidt, C.M., Hruban, R.H. and Konieczny, S.F. (2007) Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Amer. J. Pathology 171: 263-273.

Konieczny, S.F. and Leach, S.D. (2007) Metaplastic metamorphoses in the mammalian pancreas. Gastroenterology 133: 2056-2059.

Nozaki, K., Ogawa, M., Williams, J.A., Lafleur, B.J., Ng, V., Drapkin, R.I., Mills, J.C., Konieczny, S.F., Nomura, S. and Goldenring, J.R. (2008) A molecular signature of gastric metaplasia arising in response to acute parietal cell loss. Gastroenterology 134:511-522.

Rovira, M., Delaspre, F., Massumi, M., Serra, S.A., Valverde, M.A., Lloreta, J., Dufresne, M., Payré, B., Konieczny, S.F., Savatier, P., Real, F.X. and Skoudy, A. (2008) Murine ES-derived pancreatic acinar cells recapitulate early stages of cell differentiation. Gastroenterology 135:1301-1310.

Jia, D., Sun, Y., and Konieczny, S.F. (2008) Mist1 regulates pancreatic acinar cell proliferation through p21CIP1/WAF1. Gastroenterology 135:1687-1697.

Sharma, R., Lee, J.S., Bettencourt, R.C., Xiao, C., Konieczny, S.F. and Won, Y.-Y. (2008) Effects of the incorportation of a hydrophobic middle block into a PEG-polycation diblock copolymer on the physicochemical and cell interaction properties of the polymer-DNA complexes. Biomacromolecules 9:3294-3307.

Habbe, N., Shi, G., Meguid, R.A., Fendrich, V., Esni, F., Chen, H., Feldmann, G., Stoffers, D.A., Konieczny, S.F., Leach, S.D. and Maitra, A. (2008) Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl. Acad. Sci. 105:18913-18918.

Shi, G., Zhu, L., Sun, Y., Bettencourt, R., Damsz, B., Hruban, R.H. and Konieczny, S.F. (2009) Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136:1368-1378.

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