1. Telomerase, Immortalization and Cancer Eric Bankaitis Cancer Bio 169 March 9, 2006
Fig.[9]

2. Overview of Telomeres and Telomerase
Kilian et al
Telomeres: terminal regions of each chromosome.
Functions:
-Protect genome
-Shield from DSB recognition.
-Regulate the cell lifespan
Fig.[9]

3. Overview of Telomeres and Telomerase
Telomere Structure[12]
-Repeating DNA sequences
-Single stranded overhang
-DNA binding proteins
-Length varies from cell type to cell type, as do the DNA binding proteins.
Fig.[9]

4. Overview of Telomeres and Telomerase
TELOMERE BINDING PROTEINS
DNA Damage Control
Stability and Structure
Length Regulators
Growth Factor Response
Apoptosis
Polymerase Co-factors
RNA dependent Polymerase
[1]

5. Overview of Telomeres and Telomerase
Telomerase Structure:
RNA dependent DNA Polymerase
Two Subunits: hTERT and hTR[1]
Mutations eliminate activity
figure[2]

6. Overview of Telomeres and Telomerase
Telomerase Function:
Maintain Telomeres!
Senescence
Crisis and the Hayflick Limit
Strong Selection in Cancer
[9]

7. Why Cells Need Telomerase
-Differentiated Tissue:
Short Telomeres
Telomerase INACTIVE
-Germ cells, stem cells, cancer cells:
Telomere Length Maintained
Telomerase ACTIVE[1]
Knockout Mice[4]:
-Normal development
-6-Generation Abonormalities:
-CIN
-Aging

8. Telomerase and Cancer Statistics
Telomerase is active in 90% of Cancer[3].

9. Mechanisms in Cancer Development
Strong Selection for Immortalization in Cancer Progression
UPREGULATION OF TELOMERASE CATALYTIC SUBUNIT!!!
Multiple Hit Model[5]
Loss of Telomerase Repressors[6]
Oncogenic activation of Positive Regulators[7]
Enhancement of hTERT transcription[7]

10. Loss of Telomerase Repressors
Differentiated Tissue: hTERT(-) Immortal Cells: hTERT(+)
-Cell Fusion Experiments[5]
-Repressor on Human Chromosome 3[5]
“Changes in the telomeric binding proteins may regulate accessibility to the 3` overhang.”[5]

11. RB/E2F Pathway involved in some cells
“E2F1 mRNA expression and hTERT mRNA expression were statistically significantly correlated in human glioblastoma cells.”
“E2F1 expression increased hTERT promoter activity in these cells.”
“We detected an interaction between E2F1 protein and hTERT promoter”[8]
hTERT=>

12. Oncogenic Activation of hTERT Expression
“Several transcription factors, including oncogene products (e.g. c-Myc) and tumor supressor gene products are able to control hTERT transcription when overexpressed.[7]”
[10]

13. Viral Activation of hTERT
“HPV E6 protein contributes to keratinocyte immortalization through trans-activation of hTERT gene transcription.”[7]
“In some hepatocellular carcinomas, the hTERT gene is a non-random integration site for the HBV genome, which cis activates hTERT transcription.”[7]

14. Treatment and Diagnostic Methods
Figure 5: TERT Expression in Colonic Tumorigenesis.  Source: Kolquist et al

15. Treatment and Diagnosis of Cancer[1]
-Inhibitors of Telomerase:
low side effects
inhibitors already exist for many viral RT’s
-Antisence RNAs
-Inhibit Telomerase Access to the Telomere
Potential Problem: ALT pathway.

16. References
1) Hahn. William C. American Society of Clinical Oncology P
2) Griffiths A., Gelbert W. Modern Genetic Analysis; Second Edition. 2003, W.H. Freeman and Co. p100.
3) Shay J and Bachetti S. European Journal of Cancer. Vol. 33, No. 5, p , 1997.
4) Greider C.W., Blasco M.A., Cell Oct 3, 91(1):
5) Shay J, Wright W, Holt S. European Journal of Cancer. Vol. 33, No. 5, p , 1997.
6) Barretr J, Oshimura M, European Journal of Cancer. Vol. 33, No. 5, pp , 1997.
7) Horikawi L, Barret J Jul’24(7): Epub 2003 May 22. PMID:
8) Alossa M, Gomez-Manzara C Nov2;97(21): PMID:
9) Jerry Shay. University of Texas, Southwestern Medical Center, Dallas USA.
10) Lodish, Molecular Cell Biology: Firth Edition. W.H. Freeman and Company, New York. p 588.