Podcast
Questions and Answers
What is one of the primary functions of telomeres in eukaryotic cells?
What is one of the primary functions of telomeres in eukaryotic cells?
What is the sequence repeated in human telomeres?
What is the sequence repeated in human telomeres?
How do telomeres behave in normal somatic cells with age?
How do telomeres behave in normal somatic cells with age?
What structure is formed at the end of a telomere to stabilize it?
What structure is formed at the end of a telomere to stabilize it?
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What does telomerase consist of?
What does telomerase consist of?
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What is associated with the phenomenon of replicative senescence?
What is associated with the phenomenon of replicative senescence?
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Which of the following proteins is NOT directly associated with telomere stabilization?
Which of the following proteins is NOT directly associated with telomere stabilization?
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What is the result of interference with telomerase activity in cancer cells?
What is the result of interference with telomerase activity in cancer cells?
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What is a characteristic feature of telomeres found in cancerous and germ cells?
What is a characteristic feature of telomeres found in cancerous and germ cells?
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What technique is used to study the location of telomeres?
What technique is used to study the location of telomeres?
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What is the primary role of Ang1 in vascular integrity?
What is the primary role of Ang1 in vascular integrity?
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What distinguishes Ang2's function from Ang1 in terms of vascular integrity?
What distinguishes Ang2's function from Ang1 in terms of vascular integrity?
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Which of the following statements accurately describes the angiogenic switch?
Which of the following statements accurately describes the angiogenic switch?
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Which method did Rakesh Jain’s group pioneer for studying angiogenesis?
Which method did Rakesh Jain’s group pioneer for studying angiogenesis?
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Which of the following is considered a pro-angiogenic factor?
Which of the following is considered a pro-angiogenic factor?
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How do statins function in the context of angiogenesis?
How do statins function in the context of angiogenesis?
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What is the role of TIE-2 in endothelial cells?
What is the role of TIE-2 in endothelial cells?
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Which proteins are upregulated leading to replicative senescence due to signals from shortened telomeres?
Which proteins are upregulated leading to replicative senescence due to signals from shortened telomeres?
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Which of the following correctly identifies a consequence of shifting the balance between pro-angiogenic and anti-angiogenic factors?
Which of the following correctly identifies a consequence of shifting the balance between pro-angiogenic and anti-angiogenic factors?
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What is a known function of anti-angiogenic factors?
What is a known function of anti-angiogenic factors?
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What mechanism do murine cells primarily use to bypass senescence in culture conditions?
What mechanism do murine cells primarily use to bypass senescence in culture conditions?
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Which cellular event is primarily studied using the rabbit corneal pocket assay?
Which cellular event is primarily studied using the rabbit corneal pocket assay?
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What occurs in human cells that reach the Hayflick limit due to replicative senescence?
What occurs in human cells that reach the Hayflick limit due to replicative senescence?
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What is a consequence of continuing to divide with unprotected chromosome ends?
What is a consequence of continuing to divide with unprotected chromosome ends?
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Which of the following describes the role of p19ARF in cellular stress response?
Which of the following describes the role of p19ARF in cellular stress response?
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What is the primary way cancer cells maintain telomere length for continued growth?
What is the primary way cancer cells maintain telomere length for continued growth?
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Which process contributes to the genomic instability observed in early carcinogenesis?
Which process contributes to the genomic instability observed in early carcinogenesis?
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How does telomere dysfunction affect the apoptotic pathway?
How does telomere dysfunction affect the apoptotic pathway?
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What is the effect of dysfunctional telomeres on gene dosage during tumor development?
What is the effect of dysfunctional telomeres on gene dosage during tumor development?
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In which stage of cancer progression is telomerase reactivation most critical?
In which stage of cancer progression is telomerase reactivation most critical?
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Study Notes
Telomeres and Cancer
- Telomeres: Located at the ends of chromosomes in eukaryotes
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Functions:
- Prevent chromosome degradation
- Prevent fusion of chromosome ends
- Allow faithful replication of linear DNA ends
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Structure:
- Unique, short repeating sequences (e.g., TTAGGG in humans)
- Repeated numerous times (500-3300 times)
- Somatic cells shorten telomeres with age, but cancer and germ cells do not
- 3' overhang strand, length varies by organism
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Telomere Stabilization:
- G-rich single-stranded overhang participates in G-quartet and T-loop structures
- T-loop: Human telomeres adopt a t-loop configuration.
- Proteins (TRF-2, TRF-1, POT-1) involved in stabilizing telomeres
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Telomerase: Enzyme necessary for telomere replication
- Composed of RNA template (TERC) and reverse transcriptase (TERT)
- Uses leading strand to prime new DNA synthesis
- DNA polymerase fills lagging strand
- Telomerase activity often elevated in cancer cells
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Replicative Senescence (Hayflick Limit):
- Telomere shortening during cell division eventually triggers senescence
- Cells in culture stop dividing after a set number of doublings
- Senescent cells display specific characteristics (e.g., altered markers, SA-B-galactosidase activity, SASP)
- Telomere shortening can induce senescence despite growth factors and glucose
- Upregulates Rb, p53, p16Ink4A
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Cancer Bypassing Senescence:
- Expression of TERT can stabilize telomeres and immortalize cells
- Inactivation of p16/p19 INK4A locus bypasses senescence in mice
- Inactivation of p19ARF is often associated with mouse cell bypassing of senescence
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Telomere Senescence Induction:
- Can be triggered by telomere erosion or cellular stress signals activating p53 and Rb pathways
- Telomere uncovering can induce senescence
- Increased p53, p19ARF, p16INK4A, and hypo-phosphorylated RB levels characterize telomere-induced senescence
- Inhibited TRF-2 can also increase likelihood of looking like cells in replicative senescence
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Telomere Dysfunction and Genomic Instability:
- Continued division with unprotected chromosome ends leads to crisis
- Cells in crisis undergo chromosomal breakage, rearrangements, and genomic amplifications/deletions (BFB cycles)
- Extensive damage leads to a genetic disaster
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DNA Damage Response:
- Telomere instability can cause apoptosis or induce telomerase reactivation or ALT (alternative lengthening of telomeres)
- Most cancers reactivate TERT, while some use ALT pathways
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Cancer Development:
- Telomere shortening due to continuous turnover can lead to telomere attrition and subsequent genomic instability
- Telomerase reactivation at the carcinoma-in-situ stage provides stability enabling further mutations during progression to invasive and metastatic cancers
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P53 & Murine Studies:
- Loss of p53 can mitigate growth arrest and apoptotic responses following mTERC knockout (causing telomere dysfunction)
Angiogenesis
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Definition: Formation of new blood vessels from pre-existing ones
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Importance: Critical for tumor growth and spread of anti-cancer therapies/drugs
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Cells Involved:
- Vascular Endothelial Cells (ECs): Form the lining of blood vessels
- Peri-Endothelial Cells (pericytes): Support ECs
- Smooth Muscle Cells: Support blood vessels
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Lymphatic System:
- Drains interstitial fluid
- Lymphatic vessels are similar to capillaries but lack pericytes and smooth muscle support cells
- Lymph nodes filter lymph, aggregate immune cells and mount immune responses
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Angiogenesis in Development:
- Similar steps in embryogenesis
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Signaling Molecules:
- VEGF: Major stimulator of angiogenesis
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Angiopoietins: (Ang1 & Ang2) bind to TIE-2 receptor
- Ang1 promotes vessel stability by recruiting pericytes
- Ang2 disrupts vessel structure and contributes to endothelial cell migration
- PDGF and others
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Factors Affecting Angiogenesis:
- Pro-angiogenic: VEGF, bFGF, PDGF
- Anti-angiogenic factors: Counteract pro-angiogenic factors balancing the system
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Angiogenic Switch:
- Transition from angiogenic quiescence to active new blood vessel formation
- Triggered by altered balance between pro- and anti-angiogenic factors
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Anti-cancer Therapies:
- Targeting angiogenesis by upregulating or introducing anti-angiogenic compounds
- Statins can interfere with blood vessel formation
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Description
Dive into the fascinating world of telomeres and their critical role in cancer. This quiz covers the structure, functions, and stabilization mechanisms of telomeres, as well as the importance of the enzyme telomerase in DNA replication. Challenge your understanding of cellular biology and genetics through this engaging quiz.
