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   Biochemistry and Molecular Genetics Faculty.

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Contact Information

University Of Illinois at Chicago

Dept. Of Biochemistry and

Molecular Genetics

 

900 S. Ashland (M/C 669)
Chicago, IL 60607
tel: 312-996-7670
fax: 312-413-0353

 

Dr. Angela L.Tyner
atyner@uic.edu

Major Interests:

Regulation of epithelial cell differentiation

Cell cycle regulation in regenerating tissues

PTK6: a novel intracellular tyrosine kinase expressed in epithelia

My laboratory focuses on identifying molecular mechanisms responsible for proper regulation of epithelial cell renewal. The intestinal epithelium provides an excellent system for studying cell differentiation and cell turnover. Our efforts to identify novel regulatory genes expressed in the mouse intestine resulted in the cloning of a novel protein tyrosine kinase named PTK6 (also called Brk for Breast tumor kinase, or Sik for Src-related intestinal kinase).

   
 

 

Dr. Angela L. Tyner, Professor
PhD, University of Chicago


 

PTK6 is expressed in differentiated cells in the linings of the gastrointestinal tract (tongue, esophagus, stomach, small and large intestine) and skin, and we determined that it is activated during differentiation. Although it is not expressed in the normal mammary gland, PTK6 is expressed at high levels in two-thirds of human breast tumors and breast tumor cell lines examined. PTK6 is expressed in nuclei of normal prostate epithelial cells, but then relocalized to the cytoplasm in prostate tumors. Using transgenic and knockout mice, we are currently trying to determine the role that PTK6 plays during normal epithelial cell differentiation and in cancer. In addition, we are using biochemical approaches to identify PTK6 substrates and interacting proteins. We are also examining the expression and activity of PTK6 in human breast, prostate and colon tumors to determine whether it can be used as a prognostic or diagnostic cancer marker.

Cyclin kinase inhibitors and control of cell proliferation

Cyclin dependent kinase inhibitors (CKIs), which bind and inhibit the activity of cyclin dependent kinases (Cdks), play key roles in negatively regulating cell proliferation. One of the first CKIs to be identified was p21(WAF1/CIP1), which has a broad specificity for Cdk/cyclin complexes. We have been examining the regulation and function of p21. We have determined that expression of the p21 gene is induced in a p53-independent manner in differentiating cells of the gastrointestinal tract and during liver regeneration. We are identifying cis-acting elements and trans-acting factors responsible for regulating p21 expression in these tissues.

The liver is a vital organ that performs many essential functions, and in response to injury it possesses a greater capacity to regenerate than any other organ. Liver regeneration must be stringently regulated because when hepatic regeneration is uncontrolled, hepatocellular carcinoma may develop. Carbon tetrachloride (CCl4) induces liver cell death, and it has been widely used to experimentally induce liver injury and regeneration. We have found that p21 and the related CKI p27 are differentially regulated in the liver following CCl4 induced injury. We are determining the functions of p21 and p27 during regeneration following CCl4 induced injury in mice with disrupted p21 and p27 genes. Decreased expression of p21 and p27 has been detected in human cancers, and lack of both of these critical cell cycle checkpoint proteins in the mouse may lead to increased susceptibility to developing liver tumors following liver injury. We are also examining the roles of p21 and p27 during the continuous renewal and differentiation of the intestinal epithelium in knockout mice.

SELECTED PUBLICATIONS


Haegebarth A, Bie W., Yang R., Crawford S. E., Vasiouhkhin V., Fuchs E., and A.L. Tyner. 2006. Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine. Mol. Cell. Biol. 26(13): 4949-4957.

Yang R., Bie W., Haegebarth A., and A. L. Tyner. 2006. Differential regulation of D-type cyclins in the mouse intestine. Cell Cycle 5(2):180-3.

Lukong K.E., Larocque D., Tyner A. L., Richard S. 2005. Tyrosine phosphorylation of SAM68 by BRK regulates intranuclear localization and cell cycle progression. J Biol Chem. 280(46):38639-47.

Haegebarth A., Nunez R. and A. L. Tyner. 2005. The Intracellular Tyrosine Kinase Brk Sensitizes Nontransformed Cells to Inducers of Apoptosis. Cell Cycle 4(9):1239-46.

Lim D. Y., Tyner A. L., Park J.B., Lee J. Y., Choi Y. H., and J. H. Park. 2005. Inhibition of colon cancer cell proliferation by the dietary compound conjugated linoleic acid is mediated by the CDK inhibitor p21(CIP1/WAF1). J Cell Physiol. 205(1):107-13.

Haegebarth A., Heap D., Bie W., Derry J.J., Richard S., and A.L. Tyner. 2004. The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2. J Biol Chem. 279, 54398-54404.

Jovanovic Poole A., Heap D., Carroll R.E., and A. L. Tyner. 2004. Tumor Suppressor Functions for the Cdk Inhibitor p21 in the Mouse Colon. Oncogene, 23(49):8128-34.

Watanabe K., Petro B.J., Sevandal M., Anshuman S., Jovanovic Poole, A., and A. L. Tyner. 2004. Histochemical examination of junctional epithelium in p21/p27 double knockout mice. Eur. J. Oral Sci., 112(3):253-8.

Radhakrishnan S.K, Feliciano C., Najmabadi F., Kandel E., Haegebarth A., Tyner A.L. and A. L. Gartel. 2004. Constitutive expression of E2F1 leads to p21-dependent cell cycle arrest in S-phase of cell cycle. Oncogene, 23, 4173-6.

Gartel A.L., Radhakrishnan S.K., Serfas M.S.,Kwon Y.H.,and A. L. Tyner. 2004. A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues. Oncogene,23(49):8154-7.

Petro B.J. ,Tan R.C., Tyner A.L., Lingen M.W., and K. Watanabe. 2004. Differential expression of the non-receptor tyrosine kinase BRK in oral squamous cell carcinoma and normal oral epithelium. Oral Oncology, 40(10):1040-7.

Gartel A. L., Feliciano C., and A. L. Tyner. 2003. A new method for determining the status of p53 in tumor cell lines of different origin, Oncology Research, 13, 405- 408.

Serfas M.S. and A. L. Tyner. 2003. Brk, Srm, Frk, and Src42A form a distinct family of intracellular Src-like tyrosine kinases. Oncology Research 13, 409-419.

Derry J.J., Prins G.S., Ray V., and A. L. Tyner. 2003. Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells. Oncogene 22, 4212-4220.

Cho H.J., Kim W.K., Kim E.J., Jung K.C., Park S., Lee H.S., Tyner A.L., and J. H.Y. Park. 2003. Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in the HT-29 human colon cell line. Am. J. Physiol. 284, G996-G1005.

Kwon Y.H.. Jovanovic A., Serfas M.S., and A.L. Tyner. 2003. The Cdk Inhibitor p21 is required for necrosisbut it inhibits apoptosis following toxin-induced liver injury. J. Biol. Chem. 278, 30348-30355.

Tyner A .L. and A.L. Gartel. 2003. The Role of CKIs in G1 Phase Progression. In "G1 Phase progression." Johannes Boonstra, Editor. Landes Bioscience/Eureka.com and Kluwer/Plenum Publishers, pp. 58-68.

Tyner, A. L. and M. B. Omary. 2003. Signal Transduction Pathways During Oncogenesis. In "Gastrointestinal Cancers, A Companion to Sleisenger and Fordtran’s Gastrointestinal and Liver Disease" A. K. Rustgi and J. Crawford, Editors. W. B. Saunders. pp. 55-68.

Kwon Y.H.. Jovanovic A., Serfas M.S., Kiyokawa H. and A. L. Tyner. 2002. p21Waf1/Cip1 functions to maintain quiescence of p27Kip1 deficient hepatocytes. J. Biol. Chem. 277 41417-41422.

Gartel A.L., and A. L. Tyner. The role of the CDK inhibitor p21CIP1/WAF1 in Apoptosis. 2002. Molecular Cancer Therapeutics 1, 639-649.

A. L. Tyner. The BRK Tyrosine Kinase. In "The Wiley Encyclopedia of Molecular Medicine," T. E. Creighton, Editor. John Wiley & Sons. .pp. 399-401, 2002.

Gartel A.L., Ye X., Goufman E., Shianov P., Hay N., Najmabadi F., and A. L. Tyner. 2001. Myc represses the p21(Waf1/Cip1) promoter and interacts with Sp1/Sp3. Proc. Natl. Acad. Sci. USA 98:4510-5.

Kwek S. S. S., Derry, J., Tyner A. L., Shen Z., and A.V. Gudkov. 2001. Functional Analysis and intracellular localization of p53 modified by SUMO-1. Oncogene 20, 2587-99.

Gartel A.L., Goufman E., Najmabadi F., and A. L. Tyner. 2000. Sp1 and Sp3 activate p21(WAF1/CIP1) gene transcription in the Caco-2 colon adenocarcinoma cell line. Oncogene 19, 5182-5188.

Derry, J., Richard S. , Valderrama Carvaja, H., Ye X., Cochrane A. W., Vasioukhin V., Chen T., and A. L. Tyner. 2000. Sik/BRK phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability. Mol. Cell. Biol. 20, 6114-6126.

Gartel A.L., Najmabadi, F., Goufman E., and A. L. Tyner. 2000. A Role for E2F1 in Ras activation of p21(WAF1/CIP1) transcription. Oncogene 19, 961-964.

© 2007 University of Illinois at Chicago