Lecture 5: Cancer - Basis of Carcinogenesis II

Question 1

1. Oncogene + functional Tumour Suppressor Gene =

2. Oncogene + dysfunctional Tumour Suppressor Gene =

Answer 1

1. Oncogene-induced senescence

2. Uncontrolled proliferation + tumour growth

Question 2

What is a tumour suppressor?

Answer 2

Gene or protein that suppresses various hallmarks of cancers - apoptosis, proliferation, differentiation etc.

Question 3

What are the 4 protein products of tumour suppressor genes?

Answer 3

1. Transcription Factors e.g. Rb
2. Cell Cycle Inhibitors e.g. p16
3. Receptors e.g. Wnt
4. Regulator of cell response to DNA damage e.g. p53

Question 4

At what stage of the cell cycle is the decision made as to whether the cells will continue on to proliferate?
This stage is tightly regulated by what?

Answer 4

G1/S checkpoint

Retinoblastoma (Rb) protein

Question 5

Hypophosphorylated Rb + E2F (bound to each other)
—-> transcritpional ____.
Hyperphosphorylated + E2F (not bound to each other)
—-> transcriptional ____.

Retinoblastoma (Rb) + E2F —> binds to DNA —> Inhibits transcription of S-phase genes. What are 4 ways this process can be mutated? Good diagram on Slide 7

Answer 5

Inhibition
Activation

1. Rb mutations that make it lose its function
2. CDK4 and cyclin D gene amplification
3. Loss of CDK inhibitor p16
4. Viral oncoproteins that bind and inhibit Rb

Question 6

Often 2 hits of a Tumour Suppressor is required in order to inactivate both alleles. The first hit is ______ and the second through _______.

Answer 6

inherited, a somatic mutation

Question 7

Human Papilloma Virus (HPV) is strongly implicated with cervical cancer (>95% of the cancers contain HPV DNA). HPV works by inactivating 2 tumour suppressor genes. What are they?

Answer 7

1. Rb

2. p53

Question 8

CDKN2A (a Cyclin-Dependant Kinase Inhibitor) is crucial in the encoding/activation of _____ and ____. What does deletion/mutation of CDKN2A cause?
Germline mutations of CDKN2A are seen in what type of cancer(s)?
Sporadic mutations of CDKN2A are seen in what type of cancer(s)?

Answer 8

p16 and p53 (both tumour suppressor genes)
Deletion of CDKN2A means no p16 and p53 which results in very rapid and aggressive proliferation of cancer cells.

G: melanoma
S: bladder, head, neck cancers, glioblastomas.

Question 9

What is Neurofibromin-1?

What does a mutation to one of the alleles cause? To both alleles?

Answer 9

A GAP - a negative regulator of Ras, helps it to inactivate itself quicker, increases the GTPase activity of Ras, therefore a tumour suppressor gene

1 allele = benign neurofibroma, both alleles = cancer

Question 10

What is Neurofibromin-1 a.k.a. Merlin?

What does a mutation in this cause?

Answer 10

A cytoskeletal protein, links actin filaments to the membrane in nervous tissue, it controls cell-cell junctions.
Cells with NF-2 mutation result in no formation of cell-cell junctions as well as an inability to respond to arrest signals as they can not ‘feel’ each other and therefore continue to proliferate.