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HemOnc Week 3 > ICL 7.5: Cell Cycle > Flashcards

ICL 7.5: Cell Cycle Flashcards

1
Q

what happens in G1?

A

cells grow in size

duplicate some of their organelles

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2
Q

what happens in S phase?

A

DNA is replicated

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3
Q

which cells exit the cell cycle?

A
  1. quiescence - some cells may require certain enzymes to continue proliferating
  2. differentiated cells like skeletal muscles and neurons leave the cell cycle and stop proliferating
  3. senescence - caused by telomere damage, oncogene activation, oxidative stress, DNA damage - cells may actually die at the end of senescence
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4
Q

what is positive regulation of the cell cycle?

A

causes the cell cycle to proceed

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5
Q

what is negative regulation of the cell cycle?

A

the restriction point in G1 is a really important point where the cell decides if it wants to continue through the rest of the cycle

there’s also checkpoints in all the stages of the cell cycle

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6
Q

what is retinablastoma protein?

A

RB is the guardian of the restriction point in G1

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7
Q

what is p53s general role?

A

monitors G1 checkpoint

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8
Q

what is strabismus?

A

cross eyed

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9
Q

what is leukocoria?

A

reflection from a white mass within the eye, giving the appearance of a white pupil

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10
Q

what is retinoblastoma?

A

a rare malignant tumor of the retina in infants

affects infants of 18 months

rare cases of retinoblastoma in adults that usually arise from previously existing benign retinocytoma that underwent malignant transformation

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11
Q

what causes retinoblastoma?

A

normal individuals have 2 RB alleles

loss of one allele in somatic cells has no effect but loss of one allele in germ cells creates carrier with wild phenotype

loss of both alleles of the RB1 gene in somatic cells causes retinoblastoma and induces tumor formation

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12
Q

which cells are the precursors for retinoblastoma?

A

cone precursor cells are the cell of origin for retinoblastoma

you only get retinoblastoma if you lose both RB in the cone precursor cells

you won’t have retinoblastoma if you lose RB in other retinal cells

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13
Q

what are the clinical effects of retinoblastoma?

A

tumors can grow and fill the eyeball

cells can also break away from the main tumor and float through the vitreous to reach other parts of the eye where they can form more tumors

retinoblastoma cells can grow along the optic nerve and reach the brain

tumor cells can also grow through the covering layers of the eyeball and into the eye socket, eyelids and nearby tissues

tumor cells can spread to the lymph nodes and other organs

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14
Q

how do you treat retinoblastoma?

A

remove tumor cells via surgery or chemo to preserve vision in the kids!

monitor for second cancers in life

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15
Q

what are the two ways get retinoblastoma?

A
  1. heritable (40%): one mutant allele is inherited and a second somatic mutation or other alteration leads to inactivation of the remaining normal allele aka loss of heterozygosity!

multiple tumors, bilateral eyes effected, early onset

  1. sporadic (60%): both RB alleles are inactivated in a single retinal cell by two independent somatic mutations

single tumors, unilateral, later onset

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16
Q

what are the characteristics of patients with germ-line mutations in RB?

A

present with cancer at a younger age

present with multiple cancers in both eyes

have lower survival rate than patients with sporadic RB

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17
Q

what cancers are people with RB predisposed too?

A

cancer of the pineal gland

soft tissue sarcomas

osteosarcoma

melanoma

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18
Q

a 1 year old patient has bilateral strabismus and leukokoria. upon examination he had multiple tumors present in both eyes and was diagnosed with retinoblastoma. what is his cancer most likely caused by?

A

mendelian inheritance of one collective RB allele in germ cells and some somatic mutation of the other RB allele in the retinal cells

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19
Q

what can compromise RB function?

A

over-expression of CDK4/6 cyclin D complex inactivates RB

disruption of the CDKi: p16

20
Q

what does CDK do during the cell cycle?

A

they promote passage of cells through the cell cycle = positive regulation

21
Q

what CDK complex promotes G1 progression?

A

CDK4/6-cyclin D

22
Q

what CDK complex promotes G2 progression?

A

CDK2-cyclin E

23
Q

what CDK complex promotes progression through S phase?

A

CDK2-cyclin A

24
Q

what CDK complex promotes progression through G2 phase?

A

CDK1-cyclin A

25
Q

what CDK complex promotes progression through mitosis?

A

CDK1-cyclin B

26
Q

how do initiate S phase?

A

turn off RB to initiate S phase because RB is the G1 restriction point gatekeeper

RB prevents G1/S transition by blocking transcription factor family E2F that transcribes important proteins for S phase

if a mitogenic signal comes in that tells us we need cell proliferation, it will prompt CDK 4/6-cyclin D complex to phosphorylate RB

phosphorylated RB releases from E2F and allows for E2F to start transcription a little

cyclin E starts to accumulate and complexes with its CDK2 to form the next CDK-cyclin complex which further phosphorylates RB so it can no longer repress E2F

now the cells can progress into S phase

27
Q

what effect on the cell cycle would a loss of RB function have?

A

cells would more readily progress through the restriction point in G1

28
Q

42 year old patient has a malignant lump in her breast. analysis of cells from the tumor inidcate there was amplification of the gene encoding CDK4. What would this alteration do?

A

increased E2F activity by causing hyper-phosphorylation of RB

CDKs all phosphorylate RB

29
Q

what do CDKs do?

A

they phosphorylate RB

they also allow for progression through the cell cycle

30
Q

what do CDKIs do?

A

they stop cell cycle progression = negative regulation

CDKIs: p27, p21, p16

31
Q

what inhibits CDK4/6-cyclin D complex?

A

G1 phase CDK complex

inhibited by p27, p21, p16

32
Q

what inhibits the CDK2/cyclin E complex?

A

G1/S phase CDK complex

p27 and p21

33
Q

what inhibits CDK2-cyclin A?

A

S phase CDK complex

p27 and p21

34
Q

what inhibits CDK1-cyclin A complex?

A

G2 phase CDK complex

p27 and p21

35
Q

what inhibits CDK1-cyclin B complex?

A

M phase CDK complex

p27 and p21

36
Q

how do CDKIs work?

A

cyclin bind to CDK and undergo conformational change to expose active site and then there’s phosphorylation of CDK so that its active

CDKIs can also bind CDK and make it inactive

37
Q

what does p16 do?

A

it’s a CDKi that prevents phosphorylation of RB and stops cell cycle progression

it helps prevent cancer through a tumor-suppression mechanism called cellular senescence

when cells divide too many times or become damaged, increased levels of p16 causes the cells to become senescent and stop dividing which drives them into G0

p16 stops cancer cells from reproducing before they can form a tumor

38
Q

what gene codes for p16?

A

CDKN2A

39
Q

what does disruption of p16 lead to?

A

it’s a CDKi that prevents phosphorylation of RB and stops cell cycle progression

disruption of p16 leads to increased CDK4/6 cyclin D activity which phosphorylates RB thus inactivating RB and increases cell cycle progression

40
Q

a patient with a benign mole on his back has molecular analysis that shows features of senescence. what are the characteristics of the mole cells?

A

high levels of the p16 cyclin dependent kinase inhibitor and low levels of RB phosphorylation

41
Q

what is Li-Fraumeni Syndrome?

A

mutations in p53 is a cause of Li-Fraumenia syndrome, a rare form of inherited cancer

p53 acts a tumor suppressor by blocking cell cycle progression, promoting apoptosis and DNA repair upon DNA damage which prevents the proliferation of abnormal cells

loss of p53 allows for cells with damaged DNA to survive and divide, thereby propagating potentially oncogenic mutations

there’s cancer in a variety of tissues at an early age like bone, soft tissue, sarcoma, breast cancer, brain tumors, leukemia and adrenocortical carcinoma

42
Q

what’s the most commonly mutated gene in cancer?

A

p53

43
Q

what are the 4 functional domains of p53?

A

THIS IS THE ORDER OF DOMAINS LEFT TO RIGHT
1. an N- terminal transactivation domain

  1. a central sequence-specific DNA binding domain
  2. a domain for p53 tetramerization
  3. a C terminal regulatory region that has sites for post-translational modifications and protein-protein interactions
44
Q

what happens to p53 levels when there’s DNA damage?

A

p53 levels increase

DNA binding properties of p53 are activated

levels of p53 are regulated primarily post-transcriptionally like via phosphorylation and acetylation

45
Q

what does p53 sense?

A

it’s a sensor of DNA damage

p53 is a tumor suppressor that is activated by DNA damage

46
Q

what is the Li-Fraumeni Syndrome inheritance pattern?

A

autosomal dominant

you only have to lose on p53 gene to get the cancer

47
Q

what is MDM2?

A

a negative regulator of p53

MDM2 over-expression can impair the p53 pathway in cancers with wild type p53

HemOnc Week 3 (22 decks)

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