Isolation of Factors that Disrupt Critical Protein/Protein Interactions within the Telomerase Holoenzyme for Use in Breast Cancer Therapeutics
Abstract
While not expressed in most adult human tissues, high levels of telomerase activity are present in most cancers. Expression of telomerase in many primary cell cultures is sufficient to bypass normal senescence. Cellular senescence can act as a terminal growth-control checkpoint preventing the progression of pre-cancerous cells to malignancy. Blockade of telomerase activity In breast neoplasias should reintroduce this checkpoint resulting in replication-dependent senescence of proliferating cells. Therefore, telomerase antagonists could potentially control growth and metastasis of residual cancer cells after surgery and chemotherapy. We have identified the molecular chaperones p23, and hsp9O as proteins that bind to the catalytic subunit of telomerase. Blockade of this interaction inhibits assembly of active telomerase in vitro. Therefore, we anticipate that small molecules that bind hTERT and prevent association with p23 will act as telomerase antagonists in cells. We have used selective screens of a library of structurally constrained poly-peptides for those that disrupt hTERT/p23 complexes by binding directly to hTERT. Peptides isolated from this screen will be tested for inhibitory effects on telomerase activity, telomerase maintenance, and proliferative capacity. We predict that introduction of telomerase antagonists in breast cancer cells will result in the replication-dependent senescence of these cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2001
- Accession Number
- ADA396100
Entities
People
- Michael A. White
Organizations
- University of Texas at Dallas