Faculty Research

Eileen A Friedman, Ph.D.

Professor, Pathology
Adjunct Professor, Cell and Developmental Biology
2305 Weiskotten Hall
Upstate Medical University
750 East Adams Street
Syracuse, NY 13210
(315) 464-7148

Education and Clinical Training

Ph.D.: 1972, Johns Hopkins University

Research Program and Department Affiliations

Biomedical Sciences Program
Cell and Developmental Biology
Pathology

Research Interests

The role of the serine/theonine kinase Mirk/dyrk1B in cancers of the pancreas, ovary and colon.

Research Abstract

The protein kinase Mirk was cloned in our lab from colon carcinoma cells and named Minibrain related kinase. Mirk/dyrk1B is a member of the dyrk/minibrain family of serine/threonine kinases which mediate the transition from growth to differentiation in lower eukaryotes and mammals. Mirk expression is increased in response to growth factor deprivation, similar to the Mirk-related kinase, YAK1, which regulates stress response in Dictyostelium discoideum in response to nutrient starvation. Mirk is activated through the stress-activated p38MAPK signaling pathway in eukaryotic cells. The highest expression of Mirk is found in normal skeletal muscle and in certain solid tumors. We have used the myoblast differentiation system to decipher Mirk’s many functions in normal cells, and then will determine which of these functions are retained in tumors. Mirk has the unusual properties of mediating cell survival in vitro, regulating myoblast differentiation following the commitment stage of myogenesis through acting as a transcriptional activator, and maintaining untransformed cells in G0 arrest. In C2C12 myoblasts, and in nontransformed epithelial cells and fibroblasts, Mirk elongates the G0 phase of the cell cycle. Mirk stabilizes the CDK inhibitor p27kip1 by phosphorylating p27 at serine 10, and thus maintains p27 in the nucleus where it acts as a CDK2 inhibitor. Mirk maintains cells in G0 by destabilizing the G1 cyclin, cyclin D1, by phosphorylating it at threonine 288, adjacent to the GSK3ß site of threonine 286. Mirk mediates tumor cell survival in pancreatic ductal adenocarcinomas and in rhabdomyosarcoma, the most common sarcoma in children. Knockdown of Mirk levels in these cancers induces their apoptosis.

Selected Publications

1. Lee, K., Deng, X., and Friedman, E. 2000. Mirk protein kinase is a Mitogen-activated Protein Kinase substrate that mediates survival of colon cancer cells, Cancer Research, 60: 3631-3637.

2. Lim, S, Jin, K and Friedman E. 2002. Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1a. J. Biol. Chem. 277: 25040-25046.

3. Kim, G-Y, Mercer, SE, Ewton, DZ, Yan, Y, Jin, K, and Friedman, E. 2002. The stress-activated kinases p38a and jnk1 stabilize p21cip1 by phosphorylation. J. Biol. Chem 277: 29792-29802.

4.Lim, S, Zou, Y and Friedman, E. 2002. The transcriptional activator mirk/dyrk1B is sequestered by p38 MAP kinase. J. Biol Chem. 277: 49438-45.

5. Ewton, DZ, Lee, K, Deng, X, Lim, S and Friedman, E. 2003. Rapid turnover of cell cycle regulators found in Mirk/dyrk1B transfectants. Int. J. Cancer 103: 21-28.

6. Deng, X, Ewton, DZ, Pawlikowski ,B, Maimone, M, and Friedman, E. 2003. Mirk/dyrk1B is a Rho-induced kinase active in skeletal muscle differentiation. J Biol. Chem., 278:41347-41354.

7. Zou, Y, Lim, S, Lee, K, Deng, X and Friedman, E. 2003. Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met-adaptor Ran-binding protein M, J Biol. Chem., 278: 49573 - 49581.

8. Deng, X,. Mercer, SE, Sejal Shah, Ewton, DZ, and Friedman, E. 2004. J Biol Chem. 279: 22498-22504. The CDK inhibitor p27kip1 is Stabilized in G0 by Mirk/dyrk1B Kinase.

9. Zou, Y, Ewton, DZ, Deng, X, Mercer, SE and Friedman, E. 2004. J Biol Chem 279: 27790-98, Mirk/Dyrk1B Kinase destabilizes cyclin D1 by phosphorylation at Threonine 288.

10. Deng, X, Ewton, DZ, Mercer, SE, and Friedman, E. 2005. J Biol Chem 280: 4894-4905, Mirk/dyrk1B decreases the nuclear accumulation of class II histone deacetylases during skeletal muscle differentiation.

11. Jin, K, Lim, S, Mercer, SE and Friedman, E. 2005. J Biol Chem 280: 42097-42105, The survival kinase Mirk/dyrk1B is activated through Rac1-MKK3 signaling.

12. Mercer, SE, Ewton, DZ, Deng, X, Lim, S, Mazur, TR, and Friedman, E. 2005. J Biol Chem 280: 25788-25801, Mirk/dyrk1B mediates survival during the differentiation of C2C12 myoblasts.

13. Mercer, SE, Ewton, DZ, Shah, S, Naqvi, A, and Friedman, E. 2006. Cancer Res. 66:5143-5150, Mirk/dyrk1B mediates cell survival in rhabdomyosarcomas.

14. Deng, X, Ewton, DZ, Li, S, Naqvi, A, Mercer, SE, Landas, S, and Friedman, E. 2006. Cancer Res 66:4149-4158, The kinase Mirk/dyrk1b mediates cell survival in pancreatic ductal adenocarcinoma

This profile was last updated on 11/15/2007

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