Telomerase, Immortalization and

CancerEric Bankaitis

Cancer Bio 169March 9, 2006

Fig.[9]

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]

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]

Overview of Telomeres and Telomerase

TELOMERE BINDING PROTEINS

DNA Damage ControlStability and StructureLength RegulatorsGrowth Factor ResponseApoptosisPolymerase Co-factorsRNA dependent Polymerase[1]

Overview of Telomeres and Telomerase

Telomerase Structure:

RNA dependent DNA Polymerase

Two Subunits: hTERT and hTR[1]

Mutations eliminate activity

figure[2]

Overview of Telomeres and Telomerase

Telomerase Function:

Maintain Telomeres! Senescence Crisis and the Hayflick Limit Strong Selection in Cancer

[9]

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

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

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]

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]

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=>

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]

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]

Treatment and Diagnostic Methods

Figure 5: TERT Expression in Colonic Tumorigenesis.  Source: Kolquist et al

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.

References

1) Hahn. William C. American Society of Clinical Oncology. 2003. P2034-20432) 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, p787-791, 1997.4) Greider C.W., Blasco M.A., Cell. 1997 Oct 3, 91(1): 25-34.5) Shay J, Wright W, Holt S. European Journal of Cancer. Vol. 33, No. 5, p761-766, 1997. 6) Barretr J, Oshimura M, European Journal of Cancer. Vol. 33, No. 5, pp710-715, 1997.7) Horikawi L, Barret J. 2003 Jul’24(7):1167-76. Epub 2003 May 22. PMID: 12807729.8) Alossa M, Gomez-Manzara C. 2005 Nov2;97(21): 1589-600. PMID: 16264179 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.