(102)
3. Beskrive sammenhængen mellem oncogener, cellereceptorer og kræft
Scientific American, july 2003 issue; s.49
Blicher Pedersen, Kræftens biolog; s.166
Devlin, s.217 - cc.5.3
Devlin, s.952-954; fig.21.46

Cancer is the result of cumulative mutations that alter specific locations in a cell's DNA and thus change the particular proteins encoded by cancer-related genes at these spots. The mutations affect two kinds of cancer genes:

• tumor-supressor genes - normally restain cell's ability to devide and grow. Mutations in tumor-supressor genes cause growth-inhibiting proteins encoded by the genes or controlled by proteins encoded by the genes to disappear, allowing the cell to survive and continue divinding  when it should not.

• oncogenes - genes whose mutated or over-expressed products contribute to carcinogenesis.

•  

In order to understand oncogenes, one has to understand the concept of protonogenes.

Proto-oncogenes – normal, non-mutated cellular analogs of the oncogenes.

• Their protein products are transcription factors that regulate cell growth and differentiation of a normal cell

• Some proto-oncogene products cell membrane receptors that are involved in transduction of hormonal signals or recognition of cellular growth factors

Growth-stimulation of a cell is under control of proto-oncogenes, while growth-inhibition is controled by tumor-suppresor genes.

The proto-oncogenes are grouped according to their funtion and location in the cell:

• growth factors

• growth factor receptors

• nuclear proteins

• membrane proteins

Their main funtions in the cell are:

• growth

• development

• differentiation

So, if a mutation happends in a proto-oncogene, an oncogene is created. They code for proteins with abnormal function: an overactive form of a normal protein or a abnormal amount of a normal protein.

Mutation - change in the DNA seqeunce:

• point mutation or deletition - production of an overactive protein

• gene amplification or mutation of an enchancer- production of a normal protein in too big amounts

• gene fusion - production of non-functional fusion protein which is either overactive or in too big amounts

Even though each proto-oncogene i present in two copies in the cell, a mutation in only one of them can lead to cancer, since the oncogene dominates over the proto-oncogene.

There are four types of oncogenes:

1. oncogenes, that code for growth factors and receptors (active in fx. gliom, breast cancer, glioblastom)

2. oncogenes, that code for intracellular signalproteins (active in fx. breast-, bladder-, lungcancer, leucaemia)

3. oncogenes, that code for gene regulating proteins (active in fx. leucaemia, neuroblastom, glioblastom)

4. oncogenes, that code for other types of proteins (active in fx. breastcancer, sarcoma)

There are 3 ways by which oncogenes allow a cell to escape dependance on exogenous growth factors:

1.  by autocrine mechanism - where the cytoplasmtic oncogene indirectly stimultes expression of growth-factors genes and oversecretion of growth factors that act on the same cell
    

2. by receptor alteration - as already said, some proto-oncogenes code for membrane receptors, fx. growth-factor hormone receptor. if a mutation happends, and an oncogene is created, an abnoramal receptor protein is created. The protein can be a receptor that is missing its extracellular part, meaning its ligand-binding domain is missing. The receptor acts as if it is "permanently turned on" and stimulates the signal transduction pathway (fx. tyrosin-kinase pathway) as if a growth hormone is docked at the extracellular domain all the time
    

3. by transducer alteration - an oncogene that produces a mutated protein - intermediate in the signal transduction pathway between the receptor and its resultant acitivty. The protein is permanently activated (fx. a G-protein) and induces phosphorylation of other proteins or creation of second messangers.

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