| 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.
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