Rolf J Craven

Bio / Education: 

BS Biochemistry Clemson University
MS Biochemistry University of Illinois-Chicago
PhD Genetics University of North Carolina-Chapel Hill

Research Description: 

1. Keywords: sigma-2 receptor, Pgrmc1, Hpr6, cytochrome, EGFR, autophagy, P450 protein, experimental therapeutics, cancer, RNAi, biomarker

2. Description of 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. Cancer cells often utilize proteins called tyrosine kinases to send pro-growth signals within the tumor, and one of the most frequently activated tyrosine kinases in cancer is called EGFR. We have identified a protein that binds to EGFR and maintains EGFR levels at the plasma membrane. S2R (sigma-2 receptor)/Pgrmc1 (progesterone receptor membrane component 1) was originally identified as a progesterone receptor. However, S2RPgrmc1 is unrelated to steroid hormone receptors and is a cytochrome that binds to heme and forms complexes with EGFR in cancer cells, with cytochrome P450 proteins in normal cells and possibly with an unknown progesterone receptor. Our model is that S2RPgrmc1 helps to process or transport these proteins as they are being synthesized, increasing signaling.

S2RPgrmc1 is induced by carcinogenic chemicals as cells start to form tumors. We used the yeast Saccharomyces cerevisiae as a model organism and found that the yeast S2RPgrmc1 homologue provides resistance to chemicals that damage DNA. Remarkably, this function is conserved in humans, because we found that S2RPgrmc1 elevates resistance to DNA damage in cancer cells. This is important for tumors being treated with chemotherapy, and we found that gene therapy blocking S2RPgrmc1 makes cancer cells more sensitive to chemotherapy.

We have also taken several key steps in translating our laboratory research into the clinical setting:
• We found that S2RPgrmc1 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.
• We have found that S2RPgrmc1 levels correlate with patient survival in lung cancer.
• We identified elevated levels of S2RPgrmc1 in plasma from lung cancer patients, suggesting that its levels may be useful in identifying early stage lung cancer.
• We have shown that S2RPgrmc1 promotes tumor cell growth in culture, as well as anchorage-independent growth, tumor cell invasion, sub-cutaneous tumor growth and tumor metastasis in animals.
• We have found that S2RPgrmc1 elevates the activity of matrix metalloproteinases (MMPs) which increase tumor cell invasion.
• We have identified a small molecule inhibitor of Pgrmc1 that kills tumor cells and disrupts the processing and stability of EGFR.
• A number of groups have previously shown that the sigma-2 receptor is induced in cancers, and the identification of Pgrmc1 as the sigma-2 receptor introduces a spectrum of specific inhibitors that can be tested in cancer cells.
3. Ph.D. received from the University of North Carolina at Chapel Hill, December 1996.

4. Most recent publications:

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 121: 14-29 (2009). http://www.sciencedirect.com/science/article/pii/S0163725808001885
Yim, E.-Y., Peng, G., Dai, H., Hu, R., Li, K., Lu, Y., Mills, G.B., Meric-Bernstam, F., Hennessy, B.T., Craven, R.J. and Lin, S.-Y. Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell, 15: 304-314 (2009). http://www.sciencedirect.com/science/article/pii/S1535610809000439
Ahmed, I.S, Rohe, H.A., Twist, K., Mattingly, M. and Craven, R.J. Pgrmc1 (progesterone receptor membrane component 1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. Journal of Pharmacology and Experimental Therapeutics, 333: 564-573 (2010). http://jpet.aspetjournals.org/content/333/2/564.long
Ahmed, I.S., Rohe, H.J., Twist, K.E. and Craven, R.J. Pgrmc1 (progesterone receptor membrane component 1) associates with EGFR and regulates erlotinib sensitivity, Journal of Biological Chemistry, 285: 24775-24782 (2010). http://www.jbc.org/content/285/32/24775.long
Mallory, J.C. and Craven, R.J. Candida albicans Dap1p promotes ergosterol synthesis via the P450 protein Erg11p/Cyp51p, regulating susceptibility to azole antifungal drugs, morphogenesis and damage resistance. Pharmacologia 3: 179-189 (2011). http://docsdrive.com/pdfs/pharmacologia/2012/179-189.pdf
Ahmed, I.S., Chamberlain, C. and Craven, R.J. S2RPgrmc1: the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert Opinion on Medicinal Chemistry and Toxicology, 8: 361-370 (2012). http://informahealthcare.com/doi/abs/10.1517/17425255.2012.658367
Mir, S.U.R., Ahmed, I.S., Arnold, S. and Craven, R.J. Elevated Pgrmc1 (progesterone receptor membrane component 1)/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients. International Journal of Cancer 131: 1-9 (2011).
Breuer, E.-K. Y., Murph, M.M. and Craven, R.J. Biochemical Pathways in Cancer. Biochemistry Research International. 2012: 268504 (2012).
Mir, S.U.R., Jin, L. and Craven, R.J. Ngal (neutrophil gelatinase-associated lipocalin) transcription dependent on the tumor-associated sigma-2 receptor S2RPgrmc1. Journal of Biological Chemistry, 287: 14494-14501 (2012).
Ahmed, I.S., Chamberlain, C. and Craven, R.J. S2RPgrmc1: the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert Opinion on Medicinal Chemistry and Toxicology, 8: 361-370 (2012).
Jin, L. and Craven R.J. The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor. Oncogene, in press.
Mir, S.U.R., Schwarze, S., Jin, L., Zhang, J. Friend, W., Miriyala, S., St Clair, D. and Craven, R.J. Sigma-2 receptor associates with MAP1-LC3B and promotes autophagy. Autophagy, in press.

5. Present and recent members of the lab:

Ling Jin, Technician
Steve Schwarze, Researcher

PubMed Publications: 

  • Jin, L.;Craven, R.J. "The Rak/Frk tyrosine kinase associates with and internalizes the epidermal growth factor receptor." Oncogene 33, 3 (2014): 326-35. [PubMed Link] | [ Full text ]
  • Breuer, E.K.;Murph, M.M.;Craven, R.J. "Biochemical pathways in cancer." Biochemistry research international 2012, (2014): 268504. [PubMed Link] | [ Full text ]
  • Craven, R.J. "PGRMC1: a new biomarker for the estrogen receptor in breast cancer." Breast cancer research : BCR 10, 6 (2014): 113. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Lencki, R.W. "Polymorphism of acylglycerols: a stereochemical perspective." Chemical reviews 113, 10 (2013): 7402-20. [PubMed Link] | [ Full text ]
  • Mir, S.U.;Schwarze, S.R.;Jin, L.;Zhang, J.;Friend, W.;Miriyala, S.;St Clair, D.;Craven, R.J. "Progesterone receptor membrane component 1/Sigma-2 receptor associates with MAP1LC3B and promotes autophagy." Autophagy 9, 10 (2013): 1566-78. [PubMed Link] | [ Full text ]
  • Mir, S.U.;Jin, L.;Craven, R.J. "Neutrophil gelatinase-associated lipocalin (NGAL) expression is dependent on the tumor-associated sigma-2 receptor S2RPgrmc1." The Journal of biological chemistry 287, 18 (2012): 14494-501. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Lencki, R.W. "Symmetry, chirality and crystalline tendency: the polymorphism of triacylglycerols." Food & function 3, 3 (2012): 228-33. [PubMed Link] | [ Full text ]
  • Ahmed, I.S.;Chamberlain, C.;Craven, R.J. "S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling." Expert opinion on drug metabolism & toxicology 8, 3 (2012): 361-70. [PubMed Link] | [ Full text ]
  • Mir, S.U.;Ahmed, I.S.;Arnold, S.;Craven, R.J. "Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients." International journal of cancer. Journal international du cancer 131, 2 (2012): E1-9. [PubMed Link] | [ Full text ]
  • Ahmed, I.S.;Rohe, H.J.;Twist, K.E.;Craven, R.J. "Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity." The Journal of biological chemistry 285, 32 (2010): 24775-82. [PubMed Link] | [ Full text ]
  • Ahmed, I.S.;Rohe, H.J.;Twist, K.E.;Mattingly, M.N.;Craven, R.J. "Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule." The Journal of pharmacology and experimental therapeutics 333, 2 (2010): 564-73. [PubMed Link] | [ Full text ]
  • Yim, E.K.;Peng, G.;Dai, H.;Hu, R.;Li, K.;Lu, Y.;Mills, G.B.;Meric-Bernstam, F.;Hennessy, B.T.;Craven, R.J.;Lin, S.Y. "Rak functions as a tumor suppressor by regulating PTEN protein stability and function." Cancer cell 15, 4 (2009): 304-14. [PubMed Link] | [ Full text ]
  • Rohe, H.J.;Ahmed, I.S.;Twist, K.E.;Craven, R.J. "PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding." Pharmacology & therapeutics 121, 1 (2009): 14-9. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Mallory, J.C.;Hand, R.A. "Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51." The Journal of biological chemistry 282, 50 (2007): 36543-51. [PubMed Link] | [ Full text ]
  • Ranney, M.K.;Ahmed, I.S.;Potts, K.R.;Craven, R.J. "Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer." Biochimica et biophysica acta 1772, 9 (2007): 1103-11. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Lencki, R.W. "Rapid analysis of acylglycerols in low molecular weight milk fat fractions." Lipids 42, 5 (2007): 473-82. [PubMed Link] | [ Full text ]
  • Kaetzel, D.M.;Zhang, Q.;Yang, M.;McCorkle, J.R.;Ma, D.;Craven, R.J. "Potential roles of 3'-5' exonuclease activity of NM23-H1 in DNA repair and malignant progression." Journal of bioenergetics and biomembranes 38, 3-4 (2006): 163-7. [PubMed Link] | [ Full text ]
  • Crudden, G.;Chitti, R.E.;Craven, R.J. "Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs." The Journal of pharmacology and experimental therapeutics 316, 1 (2006): 448-55. [PubMed Link] | [ Full text ]
  • Mallory, J.C.;Crudden, G.;Oliva, A.;Saunders, C.;Stromberg, A.;Craven, R.J. "A novel group of genes regulates susceptibility to antineoplastic drugs in highly tumorigenic breast cancer cells." Molecular pharmacology 68, 6 (2005): 1747-56. [PubMed Link] | [ Full text ]
  • Lark, A.L.;Livasy, C.A.;Dressler, L.;Moore, D.T.;Millikan, R.C.;Geradts, J.;Iacocca, M.;Cowan, D.;Little, D.;Craven, R.J.;Cance, W. "High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype." Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 18, 10 (2005): 1289-94. [PubMed Link] | [ Full text ]
  • Mallory, J.C.;Crudden, G.;Johnson, B.L.;Mo, C.;Pierson, C.A.;Bard, M.;Craven, R.J. "Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae." Molecular and cellular biology 25, 5 (2005): 1669-79. [PubMed Link] | [ Full text ]
  • Lightfoot HM, J.;Lark, A.;Livasy, C.A.;Moore, D.T.;Cowan, D.;Dressler, L.;Craven, R.J.;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, 2 (2004): 109-16. [PubMed Link] |
  • Kurenova, E.;Xu, L.H.;Yang, X.;Baldwin AS, J.;Craven, R.J.;Hanks, S.K.;Liu, Z.G.;Cance, W.G. "Focal adhesion kinase suppresses apoptosis by binding to the death domain of receptor-interacting protein." Molecular and cellular biology 24, 10 (2004): 4361-71. [PubMed Link] | [ Full text ]
  • Park, H.B.;Golubovskaya, V.;Xu, L.;Yang, X.;Lee, J.W.;Scully S, 2nd;Craven, R.J.;Cance, W.G. "Activated Src increases adhesion, survival and alpha2-integrin expression in human breast cancer cells." The Biochemical journal 378, Pt 2 (2004): 559-67. [PubMed Link] | [ Full text ]
  • Hand, R.A.;Craven, R.J. "Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells." Journal of cellular biochemistry 90, 3 (2003): 534-47. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Lightfoot, H.;Cance, W.G. "A decade of tyrosine kinases: from gene discovery to therapeutics." Surgical oncology 12, 1 (2003): 39-49. [PubMed Link] | [ Full text ]
  • Hand, R.A.;Jia, N.;Bard, M.;Craven, R.J. "Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor." Eukaryotic cell 2, 2 (2003): 306-17. [PubMed Link] | [ Full text ]
  • Beviglia, L.;Golubovskaya, V.;Xu, L.;Yang, X.;Craven, R.J.;Cance, W.G. "Focal adhesion kinase N-terminus in breast carcinoma cells induces rounding, detachment and apoptosis." The Biochemical journal 373, Pt 1 (2003): 201-10. [PubMed Link] | [ Full text ]
  • Meyer, T.;Xu, L.;Chang, J.;Liu, E.T.;Craven, R.J.;Cance, W.G. "Breast cancer cell line proliferation blocked by the Src-related Rak tyrosine kinase." International journal of cancer. Journal international du cancer 104, 2 (2003): 139-46. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Greenwell, P.W.;Dominska, M.;Petes, T.D. "Regulation of genome stability by TEL1 and MEC1, yeast homologs of the mammalian ATM and ATR genes." Genetics 161, 2 (2002): 493-507. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Petes, T.D. "The Saccharomyces cerevisiae suppressor of choline sensitivity (SCS2) gene is a multicopy Suppressor of mec1 telomeric silencing defects." Genetics 158, 1 (2001): 145-54. [PubMed Link] | [ Full text ]
  • Xu, L.H.;Yang, X.;Bradham, C.A.;Brenner, D.A.;Baldwin AS, J.;Craven, R.J.;Cance, W.G. "The focal adhesion kinase suppresses transformation-associated, anchorage-independent apoptosis in human breast cancer cells. Involvement of death receptor-related signaling pathways." The Journal of biological chemistry 275, 39 (2000): 30597-604. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Petes, T.D. "Involvement of the checkpoint protein Mec1p in silencing of gene expression at telomeres in Saccharomyces cerevisiae." Molecular and cellular biology 20, 7 (2000): 2378-84. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Petes, T.D. "Dependence of the regulation of telomere length on the type of subtelomeric repeat in the yeast Saccharomyces cerevisiae." Genetics 152, 4 (1999): 1531-41. [PubMed Link] | [ Full text ]
  • Xu, L.H.;Yang, X.;Craven, R.J.;Cance, W.G. "The COOH-terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells." Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 9, 12 (1998): 999-1005. [PubMed Link] | [ Full text ]
  • Xu, L.H.;Owens, L.V.;Sturge, G.C.;Yang, X.;Liu, E.T.;Craven, R.J.;Cance, W.G. "Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells." Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 7, 4 (1996): 413-8. [PubMed Link] | [ Full text ]
  • Owens, L.V.;Xu, L.;Dent, G.A.;Yang, X.;Sturge, G.C.;Craven, R.J.;Cance, W.G. "Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer." Annals of surgical oncology 3, 1 (1996): 100-5. [PubMed Link] |
  • Craven, R.J.;Cance, W.G.;Liu, E.T. "The nuclear tyrosine kinase Rak associates with the retinoblastoma protein pRb." Cancer research 55, 18 (1995): 3969-72. [PubMed Link] | [ Full text ]
  • Owens, L.V.;Xu, L.;Craven, R.J.;Dent, G.A.;Weiner, T.M.;Kornberg, L.;Liu, E.T.;Cance, W.G. "Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors." Cancer research 55, 13 (1995): 2752-5. [PubMed Link] | [ Full text ]
  • Craven, R.J.;Xu, L.H.;Weiner, T.M.;Fridell, Y.W.;Dent, G.A.;Srivastava, S.;Varnum, B.;Liu, E.T.;Cance, W.G. "Receptor tyrosine kinases expressed in metastatic colon cancer." International journal of cancer. Journal international du cancer 60, 6 (1995): 791-7. [PubMed Link] |
  • Cance, W.G.;Craven, R.J.;Bergman, M.;Xu, L.;Alitalo, K.;Liu, E.T. "Rak, a novel nuclear tyrosine kinase expressed in epithelial cells." Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 5, 12 (1994): 1347-55. [PubMed Link] | [ Full text ]
  • Levedakou, E.N.;He, M.;Baptist, E.W.;Craven, R.J.;Cance, W.G.;Welcsh, P.L.;Simmons, A.;Naylor, S.L.;Leach, R.J.;Lewis, T.B. "Two novel human serine/threonine kinases with homologies to the cell cycle regulating Xenopus MO15, and NIMA kinases: cloning and characterization of their expression pattern." Oncogene 9, 7 (1994): 1977-88. [PubMed Link] |
  • Weiner, T.M.;Liu, E.T.;Craven, R.J.;Cance, W.G. "Expression of growth factor receptors, the focal adhesion kinase, and other tyrosine kinases in human soft tissue tumors." Annals of surgical oncology 1, 1 (1994): 18-27. [PubMed Link] |
  • Weiner, T.M.;Liu, E.T.;Craven, R.J.;Cance, W.G. "Expression of focal adhesion kinase gene and invasive cancer." Lancet 342, 8878 (1993): 1024-5. [PubMed Link] |
  • Cance, W.G.;Craven, R.J.;Weiner, T.M.;Liu, E.T. "Novel protein kinases expressed in human breast cancer." International journal of cancer. Journal international du cancer 54, 4 (1993): 571-7. [PubMed Link] |
  • Cance, W.G.;Craven, R.J.;Liu, E.T. "Expression polymerase chain reaction: a sensitive method for analysis of gene expression in human tumours." Surgical oncology 1, 4 (1992): 309-14. [PubMed Link] | [ Full text ]
  • Crudden, G.;Loesel, R.;Craven, R.J. "Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors." Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 26, 3 (1969): 142-6. [PubMed Link] |
  • Yang, X.H.;Hand, R.A.;Livasy, C.A.;Cance, W.G.;Craven, R.J. "Overexpression of the receptor tyrosine kinase Tie-1 intracellular domain in breast cancer." Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24, 2 (1969): 61-9. [PubMed Link] |
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