Rolf J. Craven, Ph.D.
Associate Professor;
University of North Carolina at Chapel Hill 1996
Office: 213 Combs Cancer Research Building (0096)
Lab: (859) 323-5050
Tel: (859) 323-3832
Oligonucleotide Sequences - word; pdf
Primer Sequences - word; pdf
Current Research interests
My lab is investigating signaling pathways that are induced in cancer and allow tumor cells to spread and survive outside of their normal environment. We have identified a protein that is induced in cancer and drives several phenotypes associated with tumor formation. The Pgrmc1/Hpr6 proteins were originally identified as components of a multi-protein receptor for the steroid hormone progesterone. Pgrmc1 stands for progesterone receptor membrane component 1, and Hpr6 stands for human membrane progesterone receptor. In spite of its name, Pgrmc1 does not bind to progesterone, but it associates with an unknown protein that does. The Pgrmc1 structure is unrelated to steroid hormone receptors, but shares homology with cytochromes and binds to heme. One intriguing possibility is that Pgrmc1 uses heme to transmit signals from steroid hormones, promoting cancer cell growth.
Pgrmc1 is induced by carcinogenic chemicals as cells start to form tumors. To study this in more detail, we used the yeast Saccharomyces cerevisiae as a model organism and found that the yeast Pgrmc1 homologue provides resistance to chemicals that damage DNA. Remarkably, this function is conserved in humans, because we found that Pgrmc1 elevates resistance to DNA damage in cancer cells. This is important for tumors being treated with chemotherapy, and we found that gene therapy blocking Pgrmc1 makes breast cancer cells more sensitive to chemotherapy. A group at the University of Connecticut found the same effect in ovarian cancer cells, suggesting that this is an important property of Pgrmc1 in multiple types of cancer cells. Thus, blocking the function of Pgrmc1 in cancer would likely improve the outcome of chemotherapy treatments.
We were the first to show that Pgrmc1 is induced in a variety of human tumors, including breast, lung, colon and thyroid tumors, and this result has also been confirmed by a number of other laboratories. Because Pgrmc1 is over-expressed in tumors, it is likely that Pgrmc1 performs a function in tumorigenesis even when patients have not been treated with chemotherapy. Indeed, we have shown that Pgrmc1 elevates oncogenic signaling in cancer cells, increasing the activity of the Akt anti-apoptotic protein kinase. Recent evidence indicates that Pgrmc1 also regulates other types of oncogenic signaling, as well.
Our current efforts are focused on novel ways to inhibit Pgrmc1 using techniques that can be applied to patients in the clinic.
We have three projects that we are pursuing in the lab:
We are using gene therapy with an adenovirus and siRNA (also called RNAi) to block the function of Pgrmc1 in cancer cells and reverse chemotherapeutic resistance.
We are comparing the expression of Pgrmc1 in clinical tumor specimens to understand whether Pgrmc1 expression can predict the severity of the tumor and how it responds to therapy.
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
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 68: 1748-1757 (2005).
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 316: 448-455 (2006).
Kaetzel, D.M., Zhang, Q., Yang, M., McCorkle, J.R., Ma, D., and Craven, R.J.
Potential roles of 3’-5’ exonuclease activity of NM23-H1 in DNA repair and malignant progression. J. Biomembranes and Bioenergetics 38: 163-167 (2006).
Ranney, M.K., Ahmed, I.A., Potts, K.R. and Craven, R.J.
Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer. Biochimica and Biophysica Acta 1772: 1103-11 (2007).
Craven, R.J., Mallory, J.C., and Hand, R.A.
Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51. Journal of Biological Chemistry 282: 36543-36551 (2007).
Yang, M.M., Jarrett, S.J., Craven, R. and Kaetzel, D.M.
YNK1, the yeast homolog of human metastasis suppressor NM23, is required for repair of UV radiation- and etoposide-induced DNA damage. Mutation Research, in press (2008).
Rohe, H.J., Ahmed, I.S., Twist, K.E. and Craven, R.J.
PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacology and Therapeutics, in press.
Craven, R.J. PGRMC1: a new biomarker for estrogen-responsive breast cancers. Breast Cancer Research, in press.
Present and recent members of the lab
Ikhlas Said Ali Ahmed, Graduate student
Hannah Rohe, Medical student
Katie Twist, Medical student
Kelly Potts, Medical student
Megan Messey, Undergraduate student
Clay Condley, Medical student
Melissa Ranney, Medical resident
Gerry Crudden, Senior research technician
Julia Mallory Craven, Post-doctoral fellow
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