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Module 3 > Cellular Senescence > Flashcards

Cellular Senescence Flashcards

1
Q

What is the difference between growth between primary cells and transformed cells?

A

primary cells grow for a limited time in culture then will stop growing- don’t die just persist without dividing whereas transfromed cells continue to grow

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2
Q

How did Hayflick indicate senscence?

A

described that cells have a finite replicative capacity which despite adequte space; nutrient and growth factors fail to proliferate and remain viable

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3
Q

What was the first molecular explanation for senscence?

A

telomere shortening

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4
Q

What are the telomere repeats?

A

TTAGGG repeats

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5
Q

What is the function of telomeric cap ?

A

represses DNA damage repair pathway which would normally respond to the loss of TTAGGG repeats

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6
Q

What happens to the telomere cap with progressive telomere shortening?

A

there is not enough telomere for the cap to bind exposing DNA damage resulting in sustained DNA damage signalling

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7
Q

What are the two results of sustained DNA damage signalling?

A

apoptosis or cellular senscence

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8
Q

What is the function of cellular senescence in the context of telomere shortening?

A

cell must stop dividing or will start getting DNA damage in the genome, not telomeres and risk of transformation

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9
Q

How is senescence related to iPS reprogramming?

A

the majority of cells undergo sensecence as recognise the factors provided as oncogenic which provides a significant challenge in the field

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10
Q

How is the effect of cytotoxic drugs induced senscence important?

A

in lymphomas this is one of the most important reasons for why cytotoxic drugs work as they induce senscence

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11
Q

What happens if you give a primary cell an oncogene?

A

will undergo lots of proliferation then will recognise this and undergo senescence?

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12
Q

What are the different factors leading to senescence?

A

telomere shortening; serial culture; cytotoxic drugs; oxidative stress; DNA damage; oncegene activation; iPS reprogramming

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13
Q

What is the overall function of cellular senescence?

A

maintain genomic stability

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14
Q

What is the first thing seen in response to a senscence stimulus?

A

develop lots of DNA damage response foci

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15
Q

Why is there upregulation of cylin-kinase dependent regulators in senescence?

A

to stop the cell cycle

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16
Q

What cyclin-kinase dependent regulators are upregulated in senescence?

A

p21; p53; p16

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17
Q

What happens to the DNA in cells undergoing senescence?

A

reorganise nuclear chromatin and nuclear lamina to change gene transcription

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18
Q

What do you see in senescent cells as a result of chromatin reorganisation?

A

SAHF- senescence associated heterochomatin foci

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19
Q

What happens to the lysosomes in senscent cells?

A

increased lysosome activity

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20
Q

What is the marker of increased lysosome activity in senescence

A

SA b-Gal

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21
Q

How do you know SA b-Gal isn’t a driver of senescence?

A

if knock it out, still get senescence- not a driver but a marker

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22
Q

What is the result of the altered protein metabolism in senescence?

A

releas of SASP- senescence associated secretory phenotype; also see altered mitochondrial function which is needed to produce lots more proteins

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23
Q

What are SASPs?

A

collection of things that can cross membrane- paracrine activity which can force other cells to senesce; activate inflammation programs; give GF to other cells to promote transformation

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24
Q

What was the first indication that SASP can promote transformation?

A

if culture pre-neoplastic prostate cells with senescent cells there is increased transformation

25
Q

How is senscence related to cancer?

A

one of hte most powerful barriers to cancer progression; all cancers have to have mutated p21; p16; p53 or something controlling them to develop)

26
Q

Why might be the reason for high levels of senscent cells being found in premalignant lesiosn?

A

if constantly transcribing lots of p21 or p16, this leads to mutations and transformation

27
Q

How is p53 controlled?

A

phosphorylation

28
Q

What negatively inhibits p53?

A

MDM2

29
Q

What happens when MDM2 is inhibited or deleted?

A

there is phosphorylation of p53 which stabilises it

30
Q

What does the phosphorylated form of p53 bind to?

A

promoter for CDKN1A

31
Q

What does CDKN1A encode?

A

p21

32
Q

What does p21 negatively regulate?

A

CDK4 and CDK2

33
Q

What is the effect of inhibiting CD4 and CD2?

A

Rb cannot be phosphorylated and therefore remains bound to E2F and transcription is repressed

34
Q

What is the function of E2F?

A

drives proliferation

35
Q

What encodes the p16 gene?

A

INK4A

36
Q

What controls the expression of INK4A?

A

PRC1

37
Q

What CDKs does p16 inhibit?

A

CDK4 and CDK6

38
Q

What happens if p53 or p16 are deleted?

A

completely block growth arrest

39
Q

What is the phenotype of senescent cells?

A

growth arrest; apoptosis resistant; altered gene expression

40
Q

How are senescent cells cleared?

A

recruitment of immune cells to mediate clearance

41
Q

What shows that it is immune mediated clearance that results in senescent cell removal rather than death?

A

immunodeficient mice do not clear

42
Q

What happens to immunodeficient mice who don’t clear senescent cells ?

A

grow into tumours

43
Q

How do senescent cells recruit immune cells?

A

SASP

44
Q

What receptors do senescent cells upregulate to ensure their clearance?

A

upregulate HLA-antigens and activatory NK ligands

45
Q

Give examples of activatory NK ligands?

A

MICA; MICB; ULBP1

46
Q

What is antagonist pleiotrophy?

A

when something is beneficial early in life but detrimental later in life

47
Q

How is senescence detrimental in older?

A

stem cells and their progenitors undergo senescence limiting the stem cell pool resultin in decreased effector numbers

48
Q

Which type of haematopoietic stem cells are particularly affected?

A

loss of lymphocytes but maintain transcription of myeloid cells (AML onset is 65)

49
Q

In addition to depltion of the stem cell pool, what other detrimental effects do senescent cells have?

A

SASP changes microenvironment which can include promoting tumours

50
Q

What is senescence in T cells?

A

have completely different phenotype, as do T cells in older people- maybe not true senescence but on the spctrum

51
Q

What is the result of senescent T cells?

A

have different antigen recognition- pro-autoimmune? importnat in RA?

52
Q

What shows that the effect of senescence is not just in depletion of the stem cell pool?

A

if remove the senescent cells, can improve the function of the tissue

53
Q

Give an example of a drug that preferentially targets senescent cells?

A

ABT263

54
Q

What is the benefit seen in mice given ABT263?

A

rejuvenation of aged HSCs

55
Q

What is the role of senescent cells in wound healing?

A

if remove, there is impaired regerenation

56
Q

What demonstrates that senescent cells are critical in contributing to ageing phenotype?

A

clearance of p16INK4 cells delays ageing associated disorders

57
Q

What other diseases has senescence been implicated in?

A

many others espeically age-associated pathologies. Clinical trial in depleting senescent cells in pulmonary fibrosis /

58
Q

How can senescence be used in cancer treatment?

A

if can induce senescence in cancer cells (downstream of p53 etc mutations) can induce grwoth arrest and upregulation of NK ligands so cancer is cleared

59
Q

How is senescence used embryologically?

A

remodelling in utero

Module 3 (33 decks)

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