Molecular BIology of Cancer Topics
A proto-oncogene is a normal gene which, when mutated or overexpressed, becomes an oncogene. An oncogene is a gene that contributes to malignant transformation.
Transfection of an oncogene into a cultured, nonmalignant cell line will result in focus formation/loss of contact inhibition, reduced growth factor requirements, anchorage independent growth in soft agar and the ability of the cells to form a tumor in athymic mice.
Expression of an oncogene in a transgenic mouse will lead to hyperplasia or tumor formation at a higher frequency than in control mice. The tumor formation is not immediate: there is a long latency period and other genetic changes are needed for full malignancy.
Genetic changes in human proto-oncogenes may occur by point mutation, chromosomal translocation or gene amplification. All of these genetic alterations affect the regulation of the gene or protein activity and result in continuous stimulation of cell growth signaling, even in the absence of growth factors. The oncogene or protein encoded by it are less responsive to the normal regulatory controls on their activity.
In an example of point mutation, H-ras missense mutation in codon 12 results in Gly to Val change, and the oncogenic H-Ras protein is always active.
Transcription
factor oncogenes that are silent or expressed at low levels in the progenitor
cells of a particular cancer may be activated when placed under the control
of potent enhancer elements whitin the regulatory region of a gene that is normally
highly expressed. Such is the case of the c-myc oncogene.
Most commonly, chromosomal breakpoints occur within introns, between the coding sequences of two transcription factor genes on different chromosomes, producing a fusion gene that encodes a chimeric transcription factor, or other chimeric fusion protein with altered function or activity. The regulatory sequences that drive expression of the hybrid gene are generally derived from the gene that contributes the amino-terminal amino acids, while the carboxy-terminal amino acids are derived from a gene that is not normally expressed in the progenitor cells. An important example of such chromosmal translocation is the Philadelphia chromose, in which the c-abl proto-oncogene is translocated from chromosome 9 to the bcr locus in chromosome 22. The c-able part of the fusion protein is a kinase with two SH2 homology motifs. Most human acute leukemias contain a chromosomal translocation like bdr/abl.
A locus may be amplified by repeated DNA replication. Recombination can generate tandem arrays of the amplified DNA, which can be excised from the chromosome to form double minutes. Double minutes can integrate into another chromosome and form a homogeneous staining region. Because chromosoe integration is reversible, double minutes and homogenemous staining regions are intercheangable forms of DNA. Oncogenes commonly found amplified in human tumors includer c-myc, erbB, abl and ras.
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