A presentation on Cancer Genetics discussing Oncogenes and the Ras signalling protein as an example.

Cellular Oncogenes
The cell genome is rich source of the genes that drive human cancer
The cellular genome has tens of thousands of genes.

A large catalog of cellular cancer-causing genes has been assembled. These are called oncogenes and tumor suppressor genes

Consider the H-ras gene
The oncogene that had been cloned from human bladder carcinoma cells caused transformation of NIH 3T3 cells, while its normal proto-oncogene counterpart (i.e., the normal Hras gene) lacked this ability.

A 350-bp segments from the proto-oncogene and oncogene were subjected to DNA sequence analysis.
The critical difference was extraordinarily subtle—a single base substitution in which a G (guanosine) residue in the proto-oncogene was replaced by a T (thymidine) in the oncogene.
This single base-pair replacement - a point mutation - appeared to be all that was required to convert the normal gene into a potent oncogene

The H-ras gene
This was the first time that a mutation was discovered in a gene that contributed to the growth of a human cancer.

This genetic change arose as a somatic mutation.
The importance of Ras proteins in tumors
In the 1980s, it was demonstrated that close to 30% of all solid tumors in humans show a mutation in the Ras gene.
Certain positions in the Ras protein are particularly sensitive to oncogenic mutations.
Replacement of Gly12 in the Ras protein with any of the other natural amino acids (except Pro) leads to an increase in the tumor-transforming potential of Ras protein.
RAS a switch protein

Structure and Biochemical Properties of Ras Protein
The Ras protein is a GTPase
the GTP-bound form represents the active, switched-on state
the GDP-bound form is the inactive, switched-off state

The transition between the active and inactive forms occurs in a unidirectional cycle
The Ras activation cycle

Ras On… GEF Guanine Exchange Factors
Sos protein
Is a GEF that provokes nucleotide exchange by G proteins (guanine nucleotide-binding), such as Ras.

Ras Off… GAP GTPase Activating Protein
GTPase-activating proteins (GAP), increase the rate of GTP hydrolysis of the Ras protein up to 105-fold.
reducing the lifetime of the active GTP state.
Due to this property, they function as negative regulators of the Ras protein.

Cancer Genetics
in brief series…
by Mark Temple

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