Molecular Mechanisms of Disease: Cancer - Midterm

Tumor suppressor

protects cells from becoming cancerous by regulation of cell growth and division. Mutations in these genes can lead to uncontrolled cell growth and the development of tumors.

retinoblastoma

childhood eye tumor

unilateral Rb

a single tumor in one eye

bilateral Rb

multiple tumors in both eyes

sporadic

no family history / uninherited; removal → no further risk of cancer

familial

family history of cancer / inherited; removal does not decrease risk of more cancer

Rb

tumor suppressor gene responsible for retinoblastoma

Recessive trait

both Rb alleles must be mutated to see phenotype

2 hit model

requires 2 LOF mutations to occur

loss of heterozygosity

loss of one homologous locus / loss of a gene on a homologous chromosome

what causes loss of normal allele

1. mitotic recombination

2. gene conversion

3. chromosomal nondisjunction

4. deletion

5. point mutation

mitotic recombination

chromosome segregation can result in random pairing of 2 mutant alleles

gene conversion

during replication, polymerase jumps to wrong template strand

ovarian cancer

risk allele is on X chromosome; risk is inherited from father (1 hit model)

tumor suppressor genes can be inactivated/ silenced by

methylation

critical for development of tumors

loss of genetic info

NF1

regulates Ras

APC

regulates B-catenin

VHL

regulates HIF1a

mutation of NF1

causes Ras to stay active

mutation of apc

stabilization of B-catenin

mutation of VHL

HIF1a is stabilized and induces angiogenesis gene VEGF

PI3K is a(n)

oncogene

ras is a(n)

oncogene

BCR/ABL is a(n)

oncogene

BRAF is a(n)

oncogene

B-catenin is a(n)

oncogene

NF1 is a(n)

tumor suppressor

cell cycle restriction point location

in G1 phase

restriction point

decides whether a cell should continue the cycle; proceed to S phase, remain in G1 phase or enter G0

core components of cell cycle clock

cyclins & cyclin dependent kinases

cyclin D1 required for

passing the restriction point

cyclins E required for

S phase

cyclin & CDK are inhibited by

p15, p16, p18, p19

CDK is inhibited by

p21, p27

actions of CDK inhibitors

TGFB inhibits early cancer growth but late stage continues cancer growth

mitogens promote the cell cycle by

inducing cyclin D1 and mis-localizing CDK inhibitors (p21 & p27)

Rb silences

E2F

Cyclin E silences

Rb

myc

transcription factor that governs the decision to proliferate or differentiate

no myc

cannot proliferate

p53

promotes cell cycle arrest in response to cellular damage by inducing apoptotic genes

cancer cells without functional p53

keep dividing without fixing the problem

p53 functions as a

homo-tetramer; dominant negative mutants interfere with wild type

li-fraumeni syndrome

p53 linked

rare autosomal dominant, familial

predisposes to wide variety of cancers

DNA tumor viruses inhibit

Rb, p53 and apoptosis

point mutation in p53 is

worse than p53 null

mutant p53 inhibits

wild type p53

inhibitors of p53

Mdm2 and MdmX

Mdm2/MdmX heterodimer

promotes degradation of p53/ inhibits activity by physically binding

Mdm2 is inhibited by

ARF

loss of ARF promotes

tumorigenesis

wild type p53

Mdm2 over-expression and ARF is silenced

mutant/null p53

Mdm2 normal levels and wild type ARF

Transcription factor that regulates VEGF

HIF1 alpha

extra copies of p53 causes

hypersensitivity to DNA damage; faster aging

what is apoptosis triggered by

activation of caspases

intrinsic pathway induced by

release of cytochrome c

extrinsic pathway triggered by

activation of cell death receptors

type 1 cells

don’t require cytochrome c release to die

type 2 cells

require cytochrome c release to die

cytochrome c activates

APAF-1

Apaf-1 activates

caspase-9

initiator caspases activate

executioner caspases

Bcl-XL inhibits

BAX

BH3 inhibits

BCl-XL

EGFR is a(n)

oncogene

VHL is a(n)

tumor suppressor

RTK helps with

AKT activation

HIF-1 is a(n)

oncogene

beta-catenin

part of the wnt pathway

myc is a(n)

transcription factor

Cyclin D regulates

cell cycle progression (oncogene)

If Rb dephosphorylation doesn’t occur at end of M phase, cell will _____ dividing

not stop

PTEN is a(n)

tumor suppressor

APC is a(n)

tumor suppressor

Mdm2 is a(n)

oncogene

MCL1 is a(n)

potential oncogene