Rolf J. Craven, Ph.D.

Rolf J. Craven, Ph.D.

Assistant Professor;
University of North Carolina at Chapel Hill 1996

Rolf.Craven@uky.edu

Current Research interests

My lab is developing novel ways to treat cancer. The primary treatment for cancer is to induce DNA damage in cancer cells with chemotherapy. However, chemotherapy is not uniformly effective, and the genes that control resistance to chemotherapy are poorly understood. My lab has used both genomic and genetic analyses to develop new ways to improve the effectiveness of chemotherapy.

For the genomic approach, we treated human breast cancer cells with the chemotherapeutic drug doxorubicin and identified thousands of genes that are altered by the treatment. We have focused on approximately 200 of these genes and have analyzed 10 in some detail. A subset of these genes is sharply up-regulated by multiple chemotherapeutic drugs, but only in highly malignant breast cancer cells. Furthermore, we blocked the expression of these genes using a technique called RNAi and found that this improved the effectiveness of the chemotherapeutic drugs. In the future, we will develop new ways of inhibiting these genes that can be translated into a clinical setting.

For the genetic approach, we used the yeast Saccharomyces cerevisiae to identify novel proteins that function in DNA damage resistance. This approach is also called pharmacogenomics- the study of genes that regulate responses to specific drugs. We identified Dap1, a protein that binds to heme and activates proteins that neutralize damaging agents. Dap1 is closely related to a human protein called Hpr6, and we have found that Hpr6 performs a similar function to Dap1, regulating resistance to DNA damage from chemotherapy in cancer cells. We also found that Hpr6 is activated in a variety of human tumors, indicating that Hpr6 is an important clinical target for improving the effectiveness of chemotherapy.

We have three projects that we are pursuing in the lab:

1. We are using gene therapy with an adenovirus and siRNA (also called RNAi) to block the function of Hpr6 in cancer cells and reverse chemotherapeutic resistance.

2. We are comparing the expression of Hpr6 in clinical tumor specimens to understand whether Hpr6 expression can predict the severity of the tumor and how it responds to therapy.

3. We are analyzing new groups of genes that are regulated by chemotherapeutic drugs and are developing new ways to inhibit the genes that we identify.

Selected Publications

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Craven, R.J., and Petes, T.D. (2000)
Involvement of the checkpoint protein Mec1p in silencing of gene expression at telomeres in Saccharomyces cerevisiae. Molecular and Cellular Biology, 20:2378-2384.

Craven, R.J., and Petes, T.D. (2001)
The Saccharomyces cerevisiae Suppressor of Choline Sensitivity (SCS2) gene is a multicopy suppressor of mec1 telomeric silencing defects. Genetics 158:145-154.

Craven, R.J., Greenwell, P.W., Dominska, M., and Petes, T.D. (2002)
Control of genetic stability by the Saccharomyces cerevisiae kinases Mec1p and Tel1p. Genetics 161:493-507.

Golubovskaya, V., Beviglia, L., Xu, L., Earp, H.S., Craven, R., and Cance, W. (2002)
Focal Adhesion Kinase (FAK) and Epidermal Growth Factor Receptor (EGFR) synergistically suppress death receptor-mediated apoptosis in human breast cancer cells by activating Akt and Erk 1 and 2 signaling pathways. Journal of Biological Chemistry 277:38978-38987.

Meyer, T., Xu, L., Chang, J., Liu, E.T., Craven, R.J., and Cance, W.G. (2003)
The Rak tyrosine kinase inhibits growth of human breast cancer cells. International Journal of Cancer 104:139-146.

Hand, R.A., Jia, N., Bard, M.A., and Craven, R.J. (2003)
Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor. Eukaryotic Cell 2:121-132.

Craven, R.J.* and Cance, W.G. (2003)
A decade of tyrosine kinases: from gene discovery to therapeutics. Surgical Oncology 12:39-49.

*corresponding author.

Beviglia, L., Golubovskaya, V., Xu, L., Yang, X., Craven, R.J., and Cance, W.G. (2003)
The focal adhesion kinase amino-terminal domain induces loss of adhesion and apoptosis in breast carcinoma cells. Biochemical Journal 373: 201-210.

Yang, X..H., Hand, R.A., Livasy, C.A., Cance, W.G., and Craven, R.J. (2003)
Overexpression of the receptor tyrosine kinase tie-1 intracellular domain in breast cancer. Tumor Biology 24: 61-69.

Hand, R.A. and Craven, R.J. (2003)
The Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells. Journal of Cellular Biochemistry 90:534-547.

Park, H.B., Golubovskaya, V.M., Xu, L., Yang, X., Lee, J.W., Scully, S., Craven, R.J., and Cance, W.G.
Activated Src elevated adhesion, survival and alpha-2 integrin expression in human breast cancer cells. Biochemical Journal, 378: 559-567 (2004).

Kurenova, E., Xu, L.-H., Yang, X., Baldwin, A.S., Craven, R.J., Hanks, S.K., Liu, Z.-G., and Cance, W.G.
Focal adhesion kinase suppresses apoptosis by binding to the death domain of receptor interacting protein. Molecular and Cellular Biology, 24: 4361-4371 (2004).

Lightfoot, H.M., Lark, A., Livasy, C.A., Moore, D.T., Cowan, D., Dressler, L., Craven, R.J., and Cance, W.G.
Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis. Breast Cancer Research and Treatment, 88: 109-116 (2004).

Mallory, J.C., Crudden, G., Johnson, B.L., Mo, C., Pierson, C.A., Bard, M., and Craven, R.J. Dap1p,
a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae. Molecular and Cellular Biology 25: 1669-1679 (2005).

Lark, A.L., Livasy, C.A., Dressler, L., Moore, D.T., Millikan, R.C., Geradts, J., Ioccoca, M., Cowen, D., Little, D., Craven, R.J., and Cance, W.G.
High focal adhesion kinase expression in invasive breast carcinomas is associated with aggressive phenotype. Modern Pathology 18: 131-136 (2005).

Crudden, G., Lösel, R., and Craven, R.J.
Overexpression of the cytochrome P450 activator Hpr6 (heme-1 domain protein/human progesterone receptor) in tumors. Tumor Biology 26: 142-146 (2005).

Mallory, J.C., Crudden, G., Oliva, A., Saunders, C., Stromberg, A., and Craven, R.J.
A novel group of genes associated with survival in breast cancer cells treated with anti-neoplastic drugs. Molecular Pharmacology, in press. On the web: http://molpharm.aspetjournals.org/cgi/reprint/mol.105.016519v1

Crudden, G., Chitti, R.E., and Craven, R.J.
Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs. Journal of Pharmacology and Experimental Therapeutics, in press. On the web: http://jpet.aspetjournals.org/cgi/reprint/jpet.105.094631v1

People in my lab:

• Mr. Gerry Crudden, Senior research technician

• Dr. Julia Craven, Post-doctoral fellow

• Ms. Rachel Chitti, Graduate student

• Mr. Brandon Adkins, IBS Rotation student

• Ms. Ikhlas Said Ali Ahmed, IBS Rotation student

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