Cancer is a genetic disease driven by mutant genes that produce proteins that function inappropriately. The mutant genes may be oncogenes that promote cell growth or tumor suppressor genes that inhibit growth. Mutant oncogenes produce proteins that drive uncontrolled cell growth and promote the malignant behavior of cancer cells. A cell containing a mutated oncogene can be likened to a runaway car in which the gas pedal is floored. Mutant tumor suppressor genes produce proteins that have lost their capacity to stop cell growth. Such cells have lost the brakes that stop cell growth, leaving cancer cells grow unchecked.
One gene of particular interest to the laboratory is called p53. With a name like p53, this gene may sound unassuming. However, this is far from reality, particularly insofar as cancer is concerned. p53 is considered the "guardian of the genome" because it scans the genetic material in cells for mutated genes. When p53 senses a corrupted and potentially dangerous gene, it induces the cell containing such defective genetic material to commit suicide. p53 is a first responder in protecting the body from cancer and it's quality control is lethal. The central role of p53 as a first line of defense against cancer is illustrated by the fact that in more than half of all human cancers p53 is mutated and has lost its function.
One way that p53 works is by suppressing the expression of survival genes that can allow cancers to grow and even resist therapy. Loss of p53 allows increased expression of such survival genes, thus allowing cancerous cells to propagate. Dr. Warren and two laboratory scientists, Drs. Roxana Pincheira and David Donner, have identified a new p53 target that is highly expressed in human metastatic colon cancer, but not normal tissue. p53 suppresses the expression of the gene, which encodes a novel pro-survival protein. Loss or mutation of p53 in cells allows an increased expression of the protein. Drs. Warren, Pincheira and Donner believe that p53 and the protein are master regulators that have opposite effects on whole groups of genes. Whereas p53 diminishes the expression and function of survival genes, the protein appears to have the opposite effect. The laboratory is now defining the exact role of the factor in the development, growth, and spread of colon cancer.
The identification of this factor in colon cancer offers a tantalizing lead not only into how the loss of p53 allows malignancies to survive, but more importantly, identifies a possible therapeutic target. The highly interactive team of physician-scientists and laboratory researchers in the GI Research Laboratory, and other collaborating groups at UCSF, is poised to wed molecular biology to experimental therapeutics with the hope and expectation that patients will benefit from this discovery.