Christopher Counter

Overview:

The Counter lab studies the molecular mechanisms underlying the evolution of normal cells into cancer. The lab is divided into two major areas studying key features of human cancers.

Immortalization: We have shown that the ability of cancer cells to keep dividing, or become immortal, is a fundamental aspect of tumorigenesis, and is due to elongation of telomeres. Current efforts focus on the molecular biology of telomere-binding proteins in regulating telomere length.

Proliferation: The ability of tumor cells to proliferate inappropriately is a hallmark of cancer. One gene that plays a key role in this process is the oncogene Ras. We have shown that Ras exerts its oncogenic signals through different proteins at different phases of cancer. Current studies focus on how these different pathways promote cancer and how to inhibit their activity.

Positions:

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor in Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1990

McMaster University

Ph.D. 1996

McMaster University

Postdoctoral Fellow, Whitehead Institute For Biomedical Research

Massachusetts Institute of Technology

Grants:

JUN PROTEINS IN EPIDERMAL HOMEOSTASIS AND NEOPLASIA

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Developing inhibitors of RalA function for the treatment of pancreatic cancer

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The role of dietary copper in melanoma

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Identifying phosphatidylinositol metabolism vulnerabilities in cancer pathways

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Dynamic requirements of Ras signaling during cancer

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Utility of telomerase-pot1 fusion protein in vascular tissue engineering.

While advances in regenerative medicine and vascular tissue engineering have been substantial in recent years, important stumbling blocks remain. In particular, the limited life span of differentiated cells that are harvested from elderly human donors is an important limitation in many areas of regenerative medicine. Recently, a mutant of the human telomerase reverse transcriptase enzyme (TERT) was described, which is highly processive and elongates telomeres more rapidly than conventional telomerase. This mutant, called pot1-TERT, is a chimeric fusion between the DNA binding protein pot1 and TERT. Because pot1-TERT is highly processive, it is possible that transient delivery of this transgene to cells that are utilized in regenerative medicine applications may elongate telomeres and extend cellular life span while avoiding risks that are associated with retroviral or lentiviral vectors. In the present study, adenoviral delivery of pot1-TERT resulted in transient reconstitution of telomerase activity in human smooth muscle cells, as demonstrated by telomeric repeat amplification protocol (TRAP). In addition, human engineered vessels that were cultured using pot1-TERT-expressing cells had greater collagen content and somewhat better performance in vivo than control grafts. Hence, transient delivery of pot1-TERT to elderly human cells may be useful for increasing cellular life span and improving the functional characteristics of resultant tissue-engineered constructs.
Authors
Petersen, TH; Hitchcock, T; Muto, A; Calle, EA; Zhao, L; Gong, Z; Gui, L; Dardik, A; Bowles, DE; Counter, CM; Niklason, LE
MLA Citation
Petersen, Thomas H., et al. “Utility of telomerase-pot1 fusion protein in vascular tissue engineering..” Cell Transplant, vol. 19, no. 1, 2010, pp. 79–87. Pubmed, doi:10.3727/096368909X478650.
URI
https://scholars.duke.edu/individual/pub761708
PMID
19878625
Source
pubmed
Published In
Cell Transplantation
Volume
19
Published Date
Start Page
79
End Page
87
DOI
10.3727/096368909X478650

From bread to bedside: What budding yeast has taught us about the immortalization of cancer cells

The budding yeast Saccharomyces cerevisiae is a formidable model system indeed. With the entire genome sequenced, unparalleled genetic malleability, and an eukaryotic background, this system is virtually beyond compare for studying the multitude of biological pathways that are conserved amongst eukaryotes. Importantly with regards to human cancer, many of the cellular processes of the mammalian cell can be found, admittedly in a stripped-down version, in yeast. In this regard, yeasts are fertile ground for elucidating mechanisms and identifying the key players in cellular processes. This invaluable information can then act as a guide for the cancer cell biologist attempting to navigate the analogous pathway in the far more complex and elaborate system of the mammalian cell. One example of where yeast has been used in this regard is in understanding how cancer cells acquire the ability to divide indefinitely. Here we highlight the enormous contributions made by studies performed in the model system of S. cerevisiae to our understanding of this tumourigenic process. © 2007 Springer.
Authors
Banik, SSR; Counter, CM
MLA Citation
Banik, S. S. R., and C. M. Counter. From bread to bedside: What budding yeast has taught us about the immortalization of cancer cells. Dec. 2007, pp. 123–39. Scopus, doi:10.1007/978-1-4020-5963-6_5.
URI
https://scholars.duke.edu/individual/pub1031148
Source
scopus
Published Date
Start Page
123
End Page
139
DOI
10.1007/978-1-4020-5963-6_5

Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR.

The addition of telomeric repeats to chromosome ends by the enzyme telomerase is a highly orchestrated process. Although much is known regarding telomerase catalytic activity in vitro, less is known about how this activity is regulated in vivo to ensure proper telomere elongation. One protein that appears to be involved in negatively regulating telomerase function in vivo is PinX1 because overexpression of PinX1 inhibits telomerase activity and causes telomere shortening. To understand the nature of this repression, we characterized the interactions among PinX1 and the core components of telomerase, the human telomerase reverse transcriptase (hTERT) and associated human telomerase RNA (hTR). We now show that in vitro PinX1 binds directly to the hTERT protein subunit, primarily to the hTR-binding domain, as well as to the hTR subunit. However, in a cellular context, the association of PinX1 with hTR is dependent on the presence of hTERT. Taken together, we suggest that PinX1 represses telomerase activity in vivo by binding to the assembled hTERT.hTR complex.
Authors
Banik, SSR; Counter, CM
MLA Citation
Banik, Soma S. R., and Christopher M. Counter. “Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR..” J Biol Chem, vol. 279, no. 50, Dec. 2004, pp. 51745–48. Pubmed, doi:10.1074/jbc.M408131200.
URI
https://scholars.duke.edu/individual/pub690948
PMID
15381700
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
279
Published Date
Start Page
51745
End Page
51748
DOI
10.1074/jbc.M408131200

N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo.

Most tumor cells depend upon activation of the ribonucleoprotein enzyme telomerase for telomere maintenance and continual proliferation. The catalytic activity of this enzyme can be reconstituted in vitro with the RNA (hTR) and catalytic (hTERT) subunits. However, catalytic activity alone is insufficient for the full in vivo function of the enzyme. In addition, the enzyme must localize to the nucleus, recognize chromosome ends, and orchestrate telomere elongation in a highly regulated fashion. To identify domains of hTERT involved in these biological functions, we introduced a panel of 90 N-terminal hTERT substitution mutants into telomerase-negative cells and assayed the resulting cells for catalytic activity and, as a marker of in vivo function, for cellular proliferation. We found four domains to be essential for in vitro and in vivo enzyme activity, two of which were required for hTR binding. These domains map to regions defined by sequence alignments and mutational analysis in yeast, indicating that the N terminus has also been functionally conserved throughout evolution. Additionally, we discovered a novel domain, DAT, that "dissociates activities of telomerase," where mutations left the enzyme catalytically active, but was unable to function in vivo. Since mutations in this domain had no measurable effect on hTERT homomultimerization, hTR binding, or nuclear targeting, we propose that this domain is involved in other aspects of in vivo telomere elongation. The discovery of these domains provides the first step in dissecting the biological functions of human telomerase, with the ultimate goal of targeting this enzyme for the treatment of human cancers.
Authors
Armbruster, BN; Banik, SS; Guo, C; Smith, AC; Counter, CM
MLA Citation
Armbruster, B. N., et al. “N-terminal domains of the human telomerase catalytic subunit required for enzyme activity in vivo..” Mol Cell Biol, vol. 21, no. 22, Nov. 2001, pp. 7775–86. Pubmed, doi:10.1128/MCB.21.22.7775-7786.2001.
URI
https://scholars.duke.edu/individual/pub690939
PMID
11604512
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
21
Published Date
Start Page
7775
End Page
7786
DOI
10.1128/MCB.21.22.7775-7786.2001

Telomerase, cell immortality, and cancer.

Authors
Harley, CB; Kim, NW; Prowse, KR; Weinrich, SL; Hirsch, KS; West, MD; Bacchetti, S; Hirte, HW; Counter, CM; Greider, CW
MLA Citation
Harley, C. B., et al. “Telomerase, cell immortality, and cancer..” Cold Spring Harb Symp Quant Biol, vol. 59, 1994, pp. 307–15. Pubmed, doi:10.1101/sqb.1994.059.01.035.
URI
https://scholars.duke.edu/individual/pub747640
PMID
7587082
Source
pubmed
Published In
Cold Spring Harbor Symposia on Quantitative Biology
Volume
59
Published Date
Start Page
307
End Page
315
DOI
10.1101/sqb.1994.059.01.035