Telomerase, the ribonucleoprotein known to synthesize and maintain chromosome-protective telomeric DNA, is upregulated in nearly all human tumors. The goal of this research is to understand, and ultimately to exploit therapeutically, this prominent and functionally important hallmark of common human cancers. The level of telomerase upregulation is correlated with tumor grade: highly malignant therapy-resistant tumor cells have higher telomerase levels than lower grade tumors. Increasing evidence suggests that the growth advantage conferred to cancer and other immortal cells by increased telomerase is due not only to its telomere maintenance role but also to function(s) of telomerase separate from this role. Therefore, to fully understand how increased telomerase elevates the survival and proliferative potential of cancer cells, the objective of this proposal i to Aim 1: understand how telomerase interacts with telomeres to promote their maintenance, focusing first on what properties of telomeres signal to cells when telomere function is compromised;
Aim 2 : define the specific distinct functions of telomerase alternatively spliced isoforms. Some of these telomerase functions involve not only the active reverse transcriptase-competent form of the full telomerase ribonucleoprotein (RNP), but also the abundantly expressed, yet poorly characterized, reverse transcriptase-incompetent b- splice variant of the hTERT protein subunit of the telomerase RNP;
Aim 3 : dissect the mechanisms of telomere maintenance signaling from the additional mechanisms through which telomerase can act, and understand their impact on important cellular signaling pathways and processes such as growth and apoptosis. Thus, the overall goal of this proposal is to test the hypothesis that the high leve of telomerase characterizing human cancer is selected during cancer progression due to the promotion by telomerase of at least three of the primary hallmarks of cancer: telomere maintenance (immortality);activating invasion and metastasis (cancer stem-like properties;epithelial to mesenchymal transition), and evasion of cell death (anti-apoptotic). Finally, Aim 4 will investigate which of these telomerase/cancer-driver pathway interactions are the critical ones for drugs that kill cancer cells, by testing a novel hypothesis - that moderate, short-term knock- down of telomerase sensitizes cancer stem-like cells to chemotherapy - and will investigate the mechanistic basis of this. The research will use cultured human cancer cells to focus on mechanistic processes within cancer cells, by experimental manipulations and investigations of their molecular consequences. This research is anticipated to generate new approaches for anti-cancer therapies.

Public Health Relevance

Cancer is a major cause of morbidity and mortality, expected to increase in the coming decades, and progress in therapies will require new cancer-specific drugs targeting the multiple cellular processes in cancer cells that interact to drive tumor progression and disease. These cancer-hallmark processes include high levels of telomerase, whose enzymatic activity is known to be essential to maintain telomeres, which protect chromosome ends. The proposed research will pursue the currently emerging understanding that the roles of telomerase also extend to promoting other crucial, cancer- driving cell pathways, and is anticipated to generate new approaches for anti-cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA096840-11
Application #
8372162
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Pelroy, Richard
Project Start
2002-09-01
Project End
2017-06-30
Budget Start
2012-08-08
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$289,759
Indirect Cost
$96,288
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Blackburn, Elizabeth H; Epel, Elissa S; Lin, Jue (2015) Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 350:1193-8
Listerman, Imke; Gazzaniga, Francesca S; Blackburn, Elizabeth H (2014) An investigation of the effects of the core protein telomerase reverse transcriptase on Wnt signaling in breast cancer cells. Mol Cell Biol 34:280-9
Gazzaniga, Francesca S; Blackburn, Elizabeth H (2014) An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity. Blood 124:3675-84
Belin, Brittany J; Cimini, Beth A; Blackburn, Elizabeth H et al. (2013) Visualization of actin filaments and monomers in somatic cell nuclei. Mol Biol Cell 24:982-94
Chen, Baohui; Gilbert, Luke A; Cimini, Beth A et al. (2013) Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell 155:1479-91
Listerman, Imke; Sun, Jie; Gazzaniga, Francesca S et al. (2013) The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis. Cancer Res 73:2817-28
Blackburn, Elizabeth H (2011) Cancer interception. Cancer Prev Res (Phila) 4:787-92
Blackburn, Elizabeth H (2011) Walking the walk from genes through telomere maintenance to cancer risk. Cancer Prev Res (Phila) 4:473-5
Stohr, Bradley A; Xu, Lifeng; Blackburn, Elizabeth H (2010) The terminal telomeric DNA sequence determines the mechanism of dysfunctional telomere fusion. Mol Cell 39:307-14
Blackburn, Elizabeth H (2010) Telomeres and telomerase: the means to the end (Nobel lecture). Angew Chem Int Ed Engl 49:7405-21

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