Transcript Breakdown in the Regulation of Telomerase: Cellular

Telomerase, Immortalization
and Cancer
Eric Bankaitis
Cancer Bio 169
March 9, 2006
Fig.[9]
Overview of Telomeres and Telomerase
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Kilian et al
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Telomeres: terminal regions of
each chromosome.
Functions:
-Protect genome
-Shield from DSB recognition.
-Regulate the cell lifespan
Fig.[9]
Overview of Telomeres and Telomerase
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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 Control
Stability and Structure
Length Regulators
Growth Factor Response
Apoptosis
Polymerase Co-factors
RNA dependent Polymerase
[1]
Overview of Telomeres and Telomerase
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Telomerase Structure:
RNA dependent DNA
Polymerase
Two Subunits: hTERT
and hTR[1]
Mutations eliminate
activity
figure[2]
Overview of Telomeres and Telomerase
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Telomerase Function:
Maintain Telomeres!
Senescence
Crisis and the Hayflick Limit
Strong Selection in Cancer
[9]
Why Cells Need Telomerase
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-Differentiated Tissue:
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-Germ cells, stem cells, cancer cells:
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Short Telomeres
Telomerase INACTIVE
Telomere Length Maintained
Telomerase ACTIVE[1]
Knockout Mice[4]:
-Normal development
-6-Generation Abonormalities:
-CIN
-Aging
Telomerase and Cancer
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Statistics
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Telomerase is active in 90% of Cancer[3].
Mechanisms in Cancer Development
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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 nonrandom 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. P2034-2043
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, 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.