5 Review Questions - Hallmarks: Immortality and Resisting Death

what is immortality?

being able to divide indefinitely

what cells have an autonomous program and what does it allow?

normal cells have an autonomous program that allows for a finite number of replication cycles

what is different about cancer cells when it comes to replicative immortality?

cancer cells have unlimited replication

what is self-renewal?

the process whereby stems cells (or progenitor cells) give rise to daughter cells with equivalent developmental potential

what is unique for cells in culture?

they typically undergo a certain number of doublings before they stop dividing and enter senescence

what is replicative immortality?

the ability of cells, like cancer cells, in culture to have unlimited replication

what is senescence?

irreversible cell cycle arrest

what does “senex” mean?

latin for “old” or “to grow old”

what are telomeres?

repeated DNA sequences and associated proteins located at the end of chromosomes

shorten upon each round of division

natural physical clock, only allow certain number of cell divisions

what is the function of telomeres?

protect the ends of chromosomes from digestion by nuclear enzyme and prevent induction of DNA repair

composed of several repeats of sequence TTAGGG

what is the hayflick limit?

when each chromosome reaches a threshold length, cells enter senescence.

what is significant for telomeres?

telomeres protect the ends of chromosomes and are centrally involved in the capability for unlimited proliferation

the length of the telomeric DNA in a cell dictates how many cell generations its progeny can pass through before telomeres are eroded

what is telomerase?

an enzyme that extends and maintains telomere length

what cells normally express telomeres?

preserved in stem cells and hematopoietic lineages (immune cells)

what are the two main components of telomerase?

a ribonucleoprotein containing telomerase reverse transcriptase (TERT) and telomerase RNA template (TERC)

describe TERC and its functions?

contains 11 complementary base pairs to the TAGGG repeats and acts as a template for the TERT to add new repeats

describe TERT and its functions

uses an RNA template (TERC) to synthesize single-stranded TTAGGG repeats

What is the significance of TERT in cancer.

by extending telomeric DNA, telomerase is able to counter the progressive telomere loss that would otherwise occur

reactivation of TERT in cancer cells mediates immortalization via telomere extension.

how is TERT expressed in cancer?

early-stage cancers of not express significant levels or telomerase

malignant tumors have high telomerase expression and evidence of reconstruction of longer telomeres

TERT expression increases with malignancy and grading

what is the most common variant of telomerase in cancer?

TERT promoter mutations (TPMs) - non-coding driver mutations

mutation sites for TPMs

C228T and C250T - creates novel binding site for transcription factors.

how do TPMs work?

transcription factors bind turn on RNA transcription, when gets translated to more TERT proteins to go elongate telomeres

how do TPMs increase telomerase expression in cancer?

they are associated with elevated TERT expression and worse overall survival in many cancers

what is another way that TERT can be overexpressed in cancer?

TERT gene amplification, chromosomal rearrangement, and promoter hypermethylation.

c-Myc oncogene in commonly overexpressed in cancers and binds to TERT promoter as well

what is apoptosis?

programmed cell death

normal function of apoptosis?

control cell numbers and rid damaged cells

ex. - skin peel of sunburn, menstruation, organ lining, tadpole losing tails

steps for apoptosis

1) apoptotic membrane blebbing

2) formation of apoptotic membrane protrusions

3) cell fragmentation

compartmentalizes cell pieces into smaller pieces to allow other cells to phagocytose the debris

what are the two main pathways of apoptosis?

extrinsic - external signals

intrinsic - internal cell stress

what factor mediates both apoptosis pathways and what is its function?

both activate caspases = proteases that cleave and break down proteins at aspartate residues (scissors)

explain extrinsic pathway

external signals received to start apoptosis

caspases target many proteins, actin (break down cytoskeleton) and DNAse (break down DNA).

what ligands activate extrinsic pathway

TNF (tumor necrosis factor)

Fas

TRAIL (tumor necrosis factor related apoptosis inducing ligand)

Explain intrinsic pathway

internal signals like DNA damage or oxidative stress start apoptosis

balance of good to bad Bcl-2 proteins flips switch to start apoptosis

pro and anti-apoptotic members

Bcl-2, Bcl-xL: anti-apoptotic (survival)

Bax, Bak: pro-apoptotic (death)

levels of pro and anti-apoptotic members in cells?

homeostasis - Bcl2 & Bax are equal

apoptosis - Bax overexpressed compared to Bcl2

survival (cancer) - Bcl2 overexpressed compared to Bax

explain how cancer cells can resist programmed cell death

increased expression of pro-survival proteins (Bcl2) and loss or pro-apoptotic proteins (Bax) are examples

some conclusions about normal cells

have a finite number of replications and divisions

are controlled and are regulated to undergo cell death if necessary

some conclusions of cancer cells

adopt mechanisms to allow an infinite number of cell division (mostly via increased telomerase expression)

adopt mechanisms to evade controlled cell death through increased expression of pro-survival proteins and others