Cell Signalling and Oncogenes Flashcards
What do all signalling pathways involve?
A chemical messenger, a receptor, and a cellular response.
Name some rapidly dividing cells
epithelia, blood cells
Name some slowly dividing cells
nerve cells
What can signal transduction result in?
Alterations in:
Cell metabolism
Gene transcription
Cell shape
What are proto-oncogenes?
Genes that code proteins that help regulate cell growth and differentiation
What is an oncogene?
A proto-oncogene that has become activated due to mutation or increased expression
What are the two factors in increasing genetic instability?
Oncogene activation
Tumour suppressor gene inactivation
What are the main initiating agents for cancer?
Environment
Genetic susceptibility
What do oncogene activation and tumour suppressor gene inactivation lead to?
Replicative senescence
Programmed cell death
Differentiation
Cell cycle checkpoint control
What are the main mutations in cancer?
Deletion, insertion, substitution, amplification and translocation
What can be deleted?
Base pair(s)
Gene
Chromosome
What can be inserted?
Base pair(s) Novel insertion of viral DNA
What can be substituted?
Base pair(s)
What can be amplified?
Gene
Region
Chromosome
What can be translocated?
Chromosome
What proteins are encoded by oncogenes that act on cell surface receptors?
Growth factors e.g. PDGF
What proteins are encoded by oncogenes that act on intracellular proteins due to extracellular signalling?
Growth factor receptors e.g. EGF receptor (erbB)
What proteins are encoded by oncogenes that are activated by transmembrane receptors?
Protein kinases or proteins that activate protein kinases e.g. Ras (ras), Raf (raf), Src (src)
What proteins are encoded by oncogenes that act within the cell?
Proteins that control the cell cycle e.g Cyclin D (bcl-1)
What proteins are encoded by oncogenes that regulate cell survival?
Proteins that affect apoptosis e.g. Bcl-2 (bcl-2)
What proteins are encoded by oncogenes that act on DNA?
Transcription factors e.g. Myc (myc)
Give 2 examples of insertional mutagenesis caused viruses?
Human papillomavirus 16/18 and cervical cancer
Hepatitis B virus and hepatocellular cancer
How common is insertional mutagenesis?
Relatively uncommon in human cancer, but has 2 high profile examples.
What chromosomal translocation occurs in chronic myeloid leukaemia?
9;22 (c-abl (9) truncated onto bcr (22))
What effect does the 9;22 CML translocation have?
Fusion protein has abnormal tyrosine kinase activity
What chromosomal translocation occurs in Burkitt’s lymphoma?
8;14 (c-myc (8) truncated onto igh (14))
What effect does the 8;14 Burkitt’s lymphoma have?
Stronger promotion of c-myc gene leading to constitutive MYC expression in B cells (gene at 14q32 = IgH locus enhancer)
How can chromosomal amplification be visualised?
FISH (n-myc amplification in neuroblastoma)
What is the main example of point mutation?
RAS gene family
At which codons can RAS genes be found to be activated by mutations?
12, 13 and 61.
Are ras mutations gain or loss of function?
Gain
What do ras genes ultimately effect?
Transcriptional regulation
Which ras is most commonly activated/mutated?
Ki-ras (12p)
What activate the ras protein?
Receptor tyrosine kinases
What kind of proteins are ras proteins?
GTP-binding monomeric switch proteins
What binds to ras to activate it?
GTP
What signalling pathway does ras activation activate?
MAP kinase pathway
What does the type of ras mutation determine?
prognosis in colorectal cancer
Which ras mutation has been associated with increased risk of recurrence and death in Dukes C?
KRAS mutation Gly12Val (G->T)
How must KRAS mutation be interpreted?
In the context of other molecular and signalling abnormalities
Why can’t RAS be blocked therapeutically?
It has widespread functions in the body so complications will occur
Give an example of where RAS is part of an important pathway
Synapic remodelling in the brain
What percentage of metastatic melanomas have a BRAF mutation?
~50%
What makes up 80% of these BRAF mutations?
V600E
What makes up 16% of these BRAF mutations?
V600K
What makes up 3% of these BRAF mutations?
V600R
When do these BRAF mutations often arise?
Early on - found in benign nevi.
Can BRAF mutations be found in other tumour types?
Yes
What is Vemurafenib?
BRAF inhibitor
Why is it called Vemurafenib?
V600E mutant Raf inhibitor - V E mu raf in
What gene is amplified in 10-30% of human breast cancers?
erbb2
What does the gene erbb2 code for?
HER-2 (Human epidermal growth factor receptor 2)
Which protein is over expressed in 10-30% of human breast cancer?
HER-2
What percentage of human breast cancers is HER-2 amplification linked with?
10-30%
What is HER-2 amplification linked to?
Poor prognosis
How can HER-2 amplification be detected?
FISH and immunohistochemistry
How is a HER-2 amplification linked breast cancer treated?
Drugs that bind to HER-2 and prevent growth
Give 2 examples of HER-2 antagonists
Trastuzumab (Herceptin)
Pertuzumab (Parjeta)
How many HER-2 receptors are there per cell in Her-2 positive breast cancer?
~1-2 million
What is trastuzumab (herceptin)?
Monoclonal antibody
When is trastuzumab given?
Often with chemo, but also alone as a prophylactic
What is trastuzumab used to treat?
Early- and late- stage breast cancer
What is pertuzumab (perjeta)?
Monoclonal antibody
When is pertuzumab given?
With trastuzumab and chemo
What is pertuzumab used to treat?
As a neoadjuvant therapy with early stage breast cancer, or to treat advanced breast cancer
What therapy is used to treat advanced breast cancer in women who have already been treated with trastuzumab and chemo?
Ado-trastuzumab emtansine (TDM-1)
What is Lapatinib?
A kinase inhibitor
What is Lapatinib used for?
Treating advanced breast cancer when trastuzumab is no longer working
