Welcome
Administration
Divisions
Faculty Directory

Research
Aging & Cancer
Cellular & Molecular
   Pathogenesis
Conservation Medicine
CTRF Cancer Genomics
Cytogenetics
Molecular Diagnostics
Oncogenomics and
   Proteomics
Paleopathology
TDAAC

Clinical Services
Anatomic Pathology
Clinical Pathology
Cytogenetics
Molecular Diagnostics
Toxicology
Transfusion Medicine

Education
General Pathology 601
Graduate Program
Resident Program
Undergraduate Medical

research goals in aging and cancer

Home | About Us | Research Goals | Research Papers | Collaborative Efforts | Resources

One of the Most Exciting Areas of Cancer Biology--The Enzyme Telomerase

The Relevance of Telomerase
Understanding Telomerase Regulation
Our Goals
Critical Insights into the Biochemical Properties
Cellular Aging
- The Senescence Checkpoint

Over the past few years, our laboratory has focused on a variety of molecular and cellular mechanisms related to prostate cancer progression, stress and aging, telomeres and telomerase, and characterization of protein folding and assembly. Using a novel prostate model system, we are investigating one of the most exciting areas of cancer biology, the enzyme telomerase.

The Relevance of Telomerase 
While not found in normal somatic cells, telomerase is associated with approximately 90% of all human malignancies, including nearly 95% of prostate cancers, making it the most prominent molecular cancer marker known. Because it is found in almost all prostate cancers, telomerase is an obvious candidate for improved diagnostic and therapeutic strategies. Understanding its functional role in tumor cells is critically important for determining how to inhibit telomerase as a means of prostate cancer treatment. 

Clearly, telomerase is relevant to a wide variety of cancers, and while one of our primary goals is dissecting the mechanisms of prostate cancer, we have funded projects and collaborations related to breast cancer and the formation of other solid tumors.

Understanding Telomerase Regulation 
In trying to understand telomerase regulation, we have recently identified the hsp90 chaperone complex as regulatory elements necessary for telomerase assembly and function both in vitro and in vivo (Holt, et al., 1999, Genes and Development). Currently, these are the only know proteins that functionally associate with human telomerase and modulate its assembly and function. The hsp90 chaperone complex has been shown to facilitate the folding of glucocorticoid receptors as well as other reverse transcriptases from viral origins and is minimally composed of hsp90, p23, hsp70, HOP (hsp organizing protein), and hsp40/ydj. 

Importantly for our studies, only about 10% of benign prostate hyperplasia (BPH) displays detectable telomerase activity, while advanced prostate carcinoma expresses high levels of telomerase (~90%). Moreover, those rare BPH specimens with telomerase have significantly lower levels of activity than advanced prostate cancers. Using our novel model system for prostate cancer progression of epithelial cells derived from the same genetic lineage, we have observed a significant increase in telomerase activity levels as immortalized prostate epithelial cells progress from non-tumorigenic to tumorigenic phenotype. 

Importantly, we find that this increase activity is in the absence of any observable change in the expression of the telomerase template RNA (hTR) or the catalytic subunit (hTERT). Since transcriptional regulation remains unchanged for the critical telomerase core components, we investigated the role of the hsp90 chaperone complex, the only known set of proteins to associate functionally with telomerase. We found that the hsp90-associated chaperones (hsp90, p23, hsp70, hsp40/ydj) are dramatically increased in parallel with tumorigenic progression, suggesting an enhanced assembly of telomerase as the mechanism for the activity increase (Akalin et al., 2001, Cancer Research). 

Our Goals 
Our goals for this project are many and have been partially funded by the Department of Defense (Dec ‘01-Dec ’04, $318,000). Using both pharmacological and genetic approaches, we will define the role of chaperones and telomerase in the progression of prostate cells toward tumorigenicity, as well as determine the importance of their interaction not only for telomerase assembly, but also for transformation. 

Related to this goal, another part of the laboratory deals with the regulation of the telomerase enzyme. As stated above, we have found that the hsp90 chaperone complex is functionally required for telomerase assembly both in vitro and in vivo. In addition to using the prostate system to study telomerase folding, we have developed a cell-free assay for dissecting the chaperone-mediated telomerase assembly process. The chaperones hsp90 and hsp70 and the co-chaperone, p23 bind specifically to the protein subunit of telomerase, hTERT, and influence its proper assembly with the template RNA, hTR. 

Critical Insight into the Biochemical Properties 
Interestingly, while hsp70 appears to dissociate from the complex upon proper conformational folding, hsp90 and p23 remain functionally associated with active telomerase, which differs from other hsp90 targets that are only transiently associated with chaperones (Forsythe, et al., 2001, Journal of Biological Chemistry). Our data suggest that components of the hsp90 chaperone complex, while required for telomerase assembly, remains associated with active enzyme, which may ultimately provide critical insight into the biochemical properties of telomerase assembly.

Cellular Aging 
Not only do we focus on cancer progression in a variety of model systems, one of the major focuses in the lab is telomere-based mechanisms of cellular aging. The ends of human chromosomes, known as telomeres, progressively shorten after successive cell division due to the inability of DNA polymerases to replicate to the end of a linear molecule (the "end replication model"). 

To this end, accumulating evidence implicates telomere shortening as one of the mitotic clocks that signal the onset of cellular senescence. In fact, we have shown that prevention of telomere shortening via introduction of telomerase into normal cells in culture results in prevention of cellular senescence or cellular aging (Bodnar, et al., 1998, Science), without signs of cancer associated changes with increased cell division (Morales, et al., 1999, Nature Genetics).

The Senescence Checkpoint 
As human cells approach the senescence checkpoint, they show a severe loss of responsiveness to environmental stress. We are investigating the role of an elevated stress response and its effects on telomere attrition as human cells progress toward senescence, and further assess the biologic effects of a sustained stress response during oxidative damage relative to rates of telomere erosion and overall cellular life span. 

The ultimate goal is to determine the biological pathways responsible for aging in order to exploit these mechanisms with respect to the prevention of age-related diseases and eventually organismal aging (mice and fish). 

Updated March 3, 2008