Lung Cancer Tumor suppressors and oncogenes (Fouty)

Additional material

Cancer is caused by the accumulation of genetic and ________ mutations in genes that normally play a role in cell proliferation, thus leading to uncontrolled cell growth

epigenetic

_____ cancer is the leading cause of cancer death in men and women in the united states.

Lung

Dysregulated cell cycle leading to uncontrolled cell proliferation can lead to malignant and non-malignant processes

Like atherosclerosis

Cyclin D binds

cdk4

Cyclin E binds

cdk2

Rb binds 

E2F 

cdk4/Cyclin D and cdk2/Cyclin E complex phosphorylates __ moving it out of it’s active form where it is not as tightly bound to E2F

Rb

_________ of Rb causes it to let go of E2F which is then free to bind trans activators/ promotors of genes

Hyperphosphorylation

Active and free E2F leads to expression of

genes important in proliferation

c-myc, c-myb, cdc2, and PCNA

Withdrawal of stimulation returns cell to G0 after completion of _____

mitosis

Small proteins called CDK inhibitors block cell proliferation

P21

p53, DNA damage, and oxygen radicals upregulates ___

p21 

P21 blocks the hyperphosphorylation of

Rb

CDK inhibitors block cell cycle progression 

P16 

p21 blocks cdk4/cyclin __ and ckd2/cyclin ___

D; E

p16 binds and blocks cdk_/cyclin _

4; D

p16 is missing in a lot of instances of lung cancers particularly _______ lung cancer

non-small cell and melenoma

CDK inhibitors

p16

p21

p27

Cell proliferation represents a balance between cyclin-cdk complexes and CDK inhibitors

normal cellular genes whose proteins/products participate in cell growth/proliferation

Proto-oncogenes 

any gene that encodes a protein that can induce cell transformation in culture or cancer in animals/humans

Oncogenes

most oncogenes are derived from mutated normal cellular genes

proto-oncogenes

ras gene is proto-oncogene; ras^D gene is ______

oncogene

____ Mutations Convert Proto-oncogenes Into Oncogenes

GOF

____ mutations activate cell cycle cyclins

Ras

Ras as an oncogene 

20-30% of NSCLC have a ___ mutation

Ras

Activation of cyclin __ by chromosome rearrangement

D

Chromosomal rearrangement

PTH promotor tends to be more active, so you get upregulation of cyclin D

Oncogenes stimulate _______

proliferation

Proto-oncogenes to oncogenes: ___ copy/ies of gene needs to be mutated 

1

_____ mutations in tumor suppressor genes are also oncogenic

LOF

______ copy/ies of tumor suppressor genes must be inactivated in cancer

2/Both

Inactivation of Tumor Suppressors: Retinoblastoma

2 hit theory

This second hit is called ______ and leads to loss of tumor suppressor function

LOH loss of heterozygosity

point mutation or other inactivation of one tumor suppressor allele

First hit

Deletion/mutation of remaining functioning tumor suppressor gene

Second hit

GOF

oncogene

LOF

tumor suppressor

Cyclin D

Cyclin E

Cyclin A

Cyclin dependent kinases 4 and 6

Proto-oncogenes (GOF)

p16

p21

p53

retinoblastoma

Tumor suppressors (Loss of Heterozygosity)

Disease of the cell cycle

Cancer

Introduce simian virus 40 to system its antigens Large T antigen and Small T antigen

Large T antigen blocks p53 and Rb

Small T antigen blocks pp2a (normal state inactivates AKT signaling pathway in proliferation)

(remove the brakes, knocking out 3 tumor suppressors)

It also turns on oncogenic Ras

(start the engine)

hTERT reactivation (Prevents shortening of telomeres hTERT so they can keep proliferating)

How simian virus introduction can lead to cancer

Cells only divide ____-____ times in a lifetime hayflick

40-60

HPV inactivated ____ and ____ pathways

p53 and Rb

HPV upregulates E6 binds p53 leading to degradation of p53

E7 binds to Rb inactivating it

E6

p53

E7

Rb

Genes that positively regulate cell proliferation 

Ras, EGFR, AKT, Cyclin D

Genes that negatively regulate cell proliferation 

p16^Ink4, Retinoblastoma, PTEN, p53

•Genes that control apoptosis

P53, BAX, MDM2

Genes involved in repair of damaged DNA

Breast Cancer Susceptibility Gene (BRCA)

Proto-oncogene chart

Tumor suppressor gene chart 

Key Signaling Pathways Dysregulated in Lung Cancer

Things increasing risk of lung cancer:

Smoking

Secondhand smoke

Asbestos (mesothelioma and increases risk of lung cancer especially in smokers)

Radon

Bad luck

____ dominant proto-oncogene in SCLC

MYC

____ dominant proto-oncogene in NSCLC

KRAS

CDKN2A gene encodes ____ really important in NSCLC

p16