#oncogenes

check out the overview here

ACTIVATION OF PROTO-ONCOGENES 

A proto-oncogene can become an oncogene by a relatively small modification:

an increase in protein activity 

a loss of regulation of its activity 

an increase in protein concentration, caused by an increase of protein expression

RAS

RAS is mutated/activated in up to 30% of all cancers. Ras point mutations are the single most common abnormality of human proto-oncogenes.

RAS proteins function as binary molecular switches that control intracellular signaling networks, controlling important processes such as cell proliferation, cell differentiation, cell adhesion, apoptosis, and cell migration. 

Ras is it is a single-subunit small GTPase, 

In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP)

in the "on" state, Ras is bound to guanosine triphosphate (GTP), 

MYC 

 encodes a DNA binding transcription factor

MYC binds to a DNA sequence in its target genes known as the E-box. 

represses the expression of CDK inhibitors 

activates the expression of cyclins 

also downregulates apoptosis and upregulates protein synthesis 

Tumour suppressor genes 

either dampen regulation of the cell cycle, or promote apoptosis

Via: Repression of genes essential for the continuation of the cell cycle -inhibiting cell division

Coupling the cell cycle to DNA damage - repair or apoptosis

Some proteins involved in cell adhesion prevent tumour cells from dispersing - inhibit metastasis

Two Hit model 

Unlike oncogenes, tumour suppressor genes generally follow the ‘two-hit model’ - both alleles must be affected before an effect is manifested. 

if only one allele for the gene is damaged, the second can still produce the correct protein - recessive.

P53 - The guardian of the genome

Homozygous loss of p53 is found in 70% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers. 

Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic tumors.

 Abnormalities of the TP53 gene can be inherited in Li-Fraumeni Syndrome, which increases the risk of developing various types of cancers. 

Recognises DNA damage and can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).

It can initiate apoptosis if DNA damage proves to be irreparable.

It is essential for the senescence response to short telomeres. (hayflick limit)

It is obvious, therefore, that damage or inactivation will result in a much greater risk of cancer.

BRCA1

 BRCA1 (breast cancer 1, early onset) mutations are associated with a significant increase in the risk of breast cancer . 

BRCA1 is involved in DNA damage repair, especially error-free repair of DNA double strand breaks, ubiquitination, and transcription.

 Women who have an abnormal BRCA1 gene have up to an 85% risk of developing breast cancer by age 70; and an increased risk of developing ovarian cancer 55% 

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An oncogene is a gene which, in the right circumstances, can transform a cell into a tumour cell. 

Exogenous - originating outside the body, include viral oncogenes which may be introduced into cells by tumour viruses Endogenous  - genes that are normally present in the cell but have been altered to produce the oncogene - this alteration can be called activating.

Proto-oncogenes - “dominant” (only one allele necessary),  genes that normally help cells grow. When a proto-oncogene mutates, or there are too many copies of it, it becomes permanently activated and the cell grows out of control --> tumour.

Tumour suppressor genes - “recessive”,  normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (apoptosis). These are like the brakes of a car; when inactivated, cells grow out of control --> tumour. 

The functions of oncogenes can be altered by:

point mutations 

amplifications

gene rearrangements/translocations

deletions of part or all of the chromosome

altered expression*

*Altered expression/epigenetics 

CML can be identified by many symptoms, including easy bleeding, weight loss and pain below the ribs on the left side. There is no UK-wide data for mortality rate, but it has appeared that younger people have a better chance of survival past 5 years than older people.

Gene ‘reading frames’ look at the nucleotides on DNA to see which protein needs to be coded. Translocation is the movement of genes, and can change what these frames look at. In CML, translocations cause the fusion of two reading frames, which causes a hybrid protein to be coded for. 

Significance of Oncogenes

Larry H. Bernstein, MD, FCAP, Curator

LPBI

  Epigenetics and Cancer Causing Genes

Kleon Tona    Mar 13, 2015   https://www.linkedin.com/pulse/epigenetics-cancer-causing-genes-oncogenes-kleon-tona

    I. Cancer Causing Genes? I have read an article recently that explained cancer as just plain “bad luck.” I do not believe this to be the case. There are harmful initiators…