Proto-oncogens and Tumour suppressors Flashcards
Tumour suppressors
inhibit cell cycle progression and often cause cell death or DNA repair
How can tumour suppressors cause cancer
when they become mutated
the 2 hit hypothesis and tumour suppressors
for loss of function both suppressor genes must be mutated
key tumour suppressors (6)
1) p53
2) APC
3) DCC
4) BRCA 1/2
5) Pten
6) Rb
p53 is involved with
the majority of cancers
Rb is involved with
retinoblastomas and osteogenic sarcomas
APC is involved with
colon
DCC is involved with
colon rectal
BRCA 1/2 is involved with
breast cancer and ovarian cancer
PTen is involved with
Gliomas , breast, thyroid
how does p53 act as a tumour suppressor
1) damaged DNA activates ATM
2) ATM activates Chk1/2 which phosphorylates p53
3) causes Mdm2 to unbind p53
4) p53 goes to nucleus and transcribes apoptotic proteins as well as P21 and p27
P21 and P27
cause cell cycle arrest –> DNA repair
How does Rb act as a tumour suppressor ?
when Rb is bound to E2F it prevents it from translocation tot the nucleus
- therefore cyclin E and CDK2 are not transcribed
when the Rb gene is mutated
oncogene- since it no longer prevents E2F from translocating to the nucleus
APC stands for
adenomatous polyposis coli
APC is part of
the B-catenin destruction complex
-acts by negatively regulating B-catenin 9 a cell growth factor)
when Wnt isn’t bound
APC causes the ubiquitination and phosphorylation of B-catenin meaning it is sent to the proteasome and cannot transcribed cell growth genes
Pten
Inhibits PIP3/Akt
-these usually promote cell proliferation and survival
BRCA -1/2
Act as tumour suppressors by repairing DNA and causing cell death
DCC is a tumour suppressor when
Netrin-1 isn’t bound- causes apoptosis by activating caspases
Proto-oncogenes
encode different proteins which stimulate cell division, cell survival and inhibit differentiation
porto-oncogenes mutate and become
oncogenes
basic detail of how proto oncogenes can cause cancer
1) oncogene have a gain of function
2) uncontrolled cell division
3) tumour
4) cancer
4 ways in which proto-oncogenes can mutate to oncogenes
1) deletion/ point mutation
2) regulatory mutation
3) gene amplification
4) chromosomal translocation
deletion and point mutations
hyperactive proteins made in normal amounts
2) regulatory mutation
3) gene amplification
4) chromosomal translocation
normal protein but greatly over expressed
chromosomal translocation
hyperactive fusion protein
oncogenes being therapeutic targets
targeting oncogenes with drugs which can inhibit their action will half uncontrollable cell growth, preventing tumour development
Examples of proto-oncogenes
SMO, ``egfr,` raf, DCC, RAS
SMO
smoothened; a proto-oncogene involved in Hh singalong that controls skin growth
normal SMO
Hh binds to PTCH, allowing SMO to move to the cilium and activate GLI
- cell growth and development
a mutated SMO
will have its signal on the whole time, causing constant activation of GLI- constant cell growth and development- uncontrollable forth and division
EGFR (MAPK receptor)
- when over expressed: colorectal, pancreatic and lung cancer
- mutated: non-small cell lung cancer , glioblastoma
RAF
- melanoma
- papillary thyroid cancer
- colon cancer
DCC as a proto-oncogene
if this receptor is mutated to be turned not he whole time without entrain, it become a proto-oncogene
RAS
- part of MAPK cascade
- provides signal which leads to cell division
if RAS mutates –> GTP is constantly bound leading to ERK being constantly activated
RAS and which cancer
-pancreatic, colon, papillary thyroid cancer, non small cell lung cancer
