Research Experience

Transcription

1 HAKAN CAM Nationwide Children s Research Hospital 700 Children s Drive, Research Bldg. II. WA5022 Columbus, OH Phone: hakan.cam@nationwidechildrens.org Education Present Principal Investigator Nationwide Children s Hospital Columbus/OH Center of Childhood Cancer Research Assistant Professor College of Medicine, OSU Postdoctoral Fellow St.Jude Children s Research Hospital Memphis/TN Department of Biochemistry Postdoctoral Fellow St.Jude Children s Research Hospital Memphis/TN Department of Molecular Pharmacology PhD Thesis in Molecular Tumorbiology Rudolf-Virchow-Center for Experimental Biomedicine, University of Wuerzburg, Wuerzburg / Germany Master of Science in Molecular Biology Max Delbrück Center for Molecular Medicine Humboldt University, Berlin / Germany Bachelor of Science in Biology Cukurova University, Adana / Turkey Research Experience /05-Present: Principal Investigator, Nationwide Children s Hospital, Department of Childhood Cancer, Columbus, OH Research Assistant Professor, College of Medicine, Ohio State University 10/09-04/10: Postdoctoral Fellow, Department of Biochemistry, St.Jude Children s Research Hospital Memphis/TN Advisor: Dr. Gerard P. Zambetti 03/06-10/09: Postdoctoral Fellow, Department of Molecular Pharmacology, St.Jude Children s Research Hospital Memphis/TN Advisor: Dr. Peter J. Houghton 01/02-03/06: Graduate Assistant, Department of Molecular Tumorbiology, Rudolf- Virchow Center for Experimental Biomedicine, Wuerzburg/Germany, Advisor. Dr. Thorsten Stiewe 1

2 01/01-01/02: Independent Study, Department of Molecular Immunotherapy, Max Delbrück Center for Molecular Medicine, Berlin/Germany. Advisor. Dr. Kang-Hun Lee 03/00-01/01: Master Study, Department of Molecular Immunology and Gene Therapy, Max Delbrück Center for Molecular Medicine, Berlin/Germany. Advisors. Dr. Thomas Blankenstein and W. Uckert 01/00-03/00: Research Project, Department of Biochemistry, Humboldt University of Berlin/Germany. Advisor. Dr. Karl Ziegler 10/99-01/00: Research Project, Department of Microbiology, Humboldt University of Berlin/Germany. Advisor. Dr. Roman A. Siddiqui 07/99-09/99: Research Project, Department of Biotechnology, Technische University of Berlin/Germany. Advisor. Dr. Birgit Neukamm Research Seminars and Poster Presentations Research Seminar: Regulation of mtorc1 by hypoxia OSUCCC Pediatric Oncology Program, Roberts Centre, Wilmington, Ohio 2010 Poster Presentation: Role of p53 family member inhibitors ΔNp53, ΔNp63 and ΔNp73 in tumor angiogenesis. OSUCCC-James 13 th Annual Scientific Meeting Maren Cam 1 *, Hemant Bid 1 * Raushan Kurmasheva, and Hakan Cam 1,2 1. Center for Childhood Cancer, Nationwide Children s Hospital, Columbus, OH *Equally contributing authors 2. Correspondence: Poster Presentation: mtorc1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α American Association for Cancer Research, Annual Meeting 2009 Denver, CO Poster Presentation: The role of p53 family members in regulation of mtor function American Association for Cancer Research, Annual Meeting 2008 San Diego, CA Research Seminar: Complex regulation of mtor function by p53 protein American Association for Cancer Research, Annual Meeting 2007 Los Angeles, CA Research Seminar: The p53 family inhibitor ΔNp73 interferes with multiple differentiation programs Congress: Cell fate and decision 1 st International Graduate College of University Würzburg, Germany

3 Poster Presentation: p53 Family Members in Muscle Differentiation and Rhabdomyosarcoma Development 13 th International AEK/AIO Cancer Congress, Würzburg, Germany 2005 Poster Presentation: p53 Family Members in Muscle Differentiation and Rhabdomyosarcoma Development ELSO-Meeting, Dresden, Germany 2005 Poster Presentation: ΔNp73 An Inhibitor of Myogenic Differentiation in Rhabdomyosarcomas 12 th p53 Workshop Dunedin, New Zealand, 2004 Publications Regulation of mammalian target of rapamycin complex 1 (mtorc1) by hypoxia: causes and consequences. Hakan Cam 1 & Peter J. Houghton 1 Target Oncol Jun;6(2): Epub 2011 Apr 16. PubMed ID: mtorc1 signalling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α Hakan Cam 1 John Easton 1 Anthony High 2 and Peter J. Houghton 1 Molecular Cell Nov 24;40(4): PubMed ID: mtor: a critical regulator of p53 during a variety of stresses Hakan Cam & Peter J. Houghton Cellscience Jan; Vol. 4 No 3 ISSN , p53 family members in muscle differentiation and rhabdomyosarcoma development Cam H, Griesmann H, Beitzinger M, Hofmann L, Beinoraviciute-Kellner R, Sauer M, Hüttinger-Kirchhof N, Oswald C, Friedl P, Gattenlöhner S, Burek C, Rosenwald A, and Stiewe T. Cancer Cell Oct;10(4): PubMed ID: The p53 family inhibitor ΔNp73 interferes with multiple developmental programs Huttinger-Kirchhof N*, Cam H*, Griesmann H, Hofmann L, Beitzinger M, Stiewe T. *Contributed equally to the work Cell Death Differ Jan;13(1): PubMed ID: Retroviral vectors for high-level transgene expression in T lymphocytes. Engels B*, Cam H*, Schuler T, Indraccolo S, Gladow M, Baum C, Blankenstein T, Uckert W. *Contributed equally to the work Human Gene Ther Aug 10;14(12): PubMed ID: Ad Hoc Reviewing Journal of Cancer Therapy The EMBO Journal Journal of Cellular and Molecular Medicine 3

4 Membership in professional organizations Active Member of American Association of Cancer Research Comprehensive Cancer Center (OSUCCC), The Ohio State University Pediatric Cancer Working Group (PCWG), American Association of Cancer Research Children s Oncology Group References: Peter J. Houghton, Ph.D. Director, Children's Cancer Center Nationwide Children's Hospital 700 Children's Drive Columbus, OH Phone: Peter.Houghton@NationwideChildrens.org Gerard P. Zambetti, PhD Member, St. Jude Faculty Vice President and Director of Academic Programs in Biomedical Sciences Associate Director for Training and Education, Cancer Center Biochemistry MS 340 Room D4063C St. Jude Children's Research Hospital 262 Danny Thomas Place Memphis, TN gerard.zambetti@stjude.org Phone: (901) Philip Potter, PhD Associate Member, St. Jude Faculty Chemical Biology & Therapeutics MS 230, Room D-3022E St. Jude Children's Research Hospital 262 Danny Thomas Place Memphis, TN Phil.Potter@STJUDE.ORG Phone: (901)

5 Research Interests p53 family members mtor signaling p53 family members Cancer is a genetic disorder caused by mutations in genes critically involved in the control of cell proliferation. Long-lived organisms, such as humans, have evolved strategies to restrict the development of potentially malignant cells. The p53 family of tumor suppressor genes (Fig. 2) provides important defense against cancer. Activated in response to DNA damage and to oncogenic signaling the three proteins of this family - p53, p63 and p73 - cooperate to induce apoptosis and thus restrict tumor formation by eliminating potentially malignant cells. Importantly, alteration of this coordination often causes cancer. Figure 2. p53 belongs to a multigene family that also includes p63 and p73. The overall protein architecture is highly conserved from Drosophila to man, and consists of a central sequence-specific DNA binding domain (DBD), an N-terminal transactivation domain (TA) and a C-terminal oligomerization domain (OD). The highest degree of homology is seen within the DBD, where >97% of all tumorassociated p53 mutations are located. As the N-terminus is crucial for the transactivation of target genes, transactivating full-length isoforms (FLp53, TAp63 and TAp73) can be functionally distinguished from transactivation-compromised N isoforms that show anti-apoptotic and dominant-negative properties. 5

6 The most frequent mutations in cancer patients are found in the p53 tumor suppressor gene which normally functions as a "guardian of the genome" to prevent the development of tumors. Once, p53 is activated it initiates several programmes that ultimately arrest proliferation and prevent the generation of genetically-altered cells. The spectrum of p53-based cell fate decisions ranges from a transient cellcycle arrest enabling damage repair or control of cell growth (size) and metabolism for preventing the wasteful buildup of proteins and other cellular building blocks (nutrients) to an irreversible block of proliferation through senescence or apoptosis. This integrative function is assisted by p63 and p73 (Fig. 3). Figure 3. The p53 family is activated by cellular stress, hyperproliferative signals and developmental stimuli. These inputs are integrated within the p53 family in crosstalk with other cellular signaling networks to reach an appropriate cell fate decision that is executed by the selective transactivation of distinct transcriptional programmers leading to reversible cell cycle arrest, irreversible cell cycle exit (differentiation or senescence), apoptotic cell death. 6

7 Taken together, despite the striking similarities among the p53 family members, however, their roles in tumorigenesis appear to be quite different. My research therefore focuses on a comparative analysis of the three genes using genetic approaches in both cell culture and animal models to understand: - How do p53 and its family members suppress tumorigenesis? - How do the p53 family inhibitors Np73 and Np63 enhance tumor formation? - How do the p53 family members regulate gene expression? - How do the p53 family members interact with other signaling networks? - What is the function of the p53 family members in normal development? mtor signaling Mammalian TOR (mtor) is an evolutionarily conserved serine/threonine kinase that integrates signals from growth factors, nutrients, and stresses to regulate multiple processes, including mrna translation, cell-cycle progression, autophagy, and cell survival. Several lines of evidence suggest that increased signaling of the mtor pathway is involved in tumor formation (Fig. 1). In human cancer, virtually every step in the pathways upstream of mtor pathway are activated, either through overexpression of receptor tyrosine kinases (e.g. ERBB2 in breast cancer), activating mutations of PI3K (colon,gastric,and breast carcinoma), amplification of Akt2, and loss of PTEN that negatively regulates PI3K (glioblastoma, hepatocellular carcinoma, lung carcinoma, melanoma, endometrial carcinomas, and prostate cancer). In cancer prone syndromes such as tuberous sclerosis, mtor signaling is enhanced due to the loss of TSC function, and in Peutz-Jehgers syndrome inactivating mutations of LKB1 prevent activation of AMPK, the direct activator of TSC. Cancer related changes in pathways downstream of mtor are also reported. S6K is overexpressed or constitutively active in tumor cell lines and in early stages of transformation in 7

8 ovarian surface epithelium associated with BRCA1 mutations. The S6K1 gene is also amplified in some breast carcinomas, although this is not necessarily associated with overexpression. eif4e is altered in a number in a number of tumors. Progressive amplification of the eif4e gene is associated with late stage head and neck carcinoma, ductal cell breast carcinoma, and thyroid carcinoma. Levels of ei4e are elevated in some colon carcinomas in comparison to normal colon cells. The levels of eif4e are also increased in some bladder and breast cancers that have a poor outcome. Rag Figure 1. mtor signaling is dysregulated in cancer. Dysregulation of steps in the signaling pathway proximal or distal to mtor reported in human cancers are denoted by red explosions. In summary, this body of evidence suggest that deregulation of mtor pathway occurs in common diseases; including cancer and diabetes that emphasizes the importance of identifying and understanding mtor signaling. Therefore, by using genetic approaches in both cell culture and animal models, my research goals are to understand and identify: 8

9 What are new components or targets of mtor signaling network? What are the functions of the components in the mtor signaling network? How do these functions might be altered or involved in metabolic diseases and cancer? How do cells manage the regulation of mtor pathway under certain conditions? In summary, combined, my work has resulted in five publications such as in Cancer Cell, Molecular Cell and currently one in preparation. This body of work illustrates my scientific creativity and productivity, and demonstrates my potential to continue to make important discoveries in mtor signalling and in p53 family members. 9