Cancer is a leading cause of death worldwide, predicted to become the number one cause of death in the year 2010. Certain types of cancers are always associated with specific gene mutations, such as the chronic myelogenous leukemia (CML). According to Carroll, CML is caused by the fusion of genes that "[disrupt] the normal control of a potent regulatory protein called the ABL kinase" (183). The ABL kinase signals the induction of apoptosis. How would the disruption of the ABL kinase promote cancer? How does the disruption relate to the cellular checkpoints that regulate the cell cycle? Please relate your response to the theme of regulation.
The drug Gleevec targets the ABL kinase in the CML tumors. How do the CML cells become resistant to Gleevec? Also, how does the change in the ABL protein relate to the concept of the substrate-enzyme model? Please relate the response to the theme of structure vs. function. What methods should be pursued to avoid and/or treat resistant CML cells?
On the subject of ABL kinase, this online journal suggests that the kinase induces apoptosis:
http://www.pnas.org/content/94/4/1437.full
The ABL kinase is similar to a proto-oncogene (genes that code for proteins that stimulate normal cell growth and division) and also similar to an oncogene (gene) - meaning that the kinase is a potentially harmful protein that can induce cancer, "in general, an oncogene arises from a genetic change that leads to an increase in either the amount of the proto-oncogene's protein product or the intrinsic activity of each protein molecule. The genetic changes that convert proto-oncogenes to oncogenes fall into three main categories: movement of DNA within the genome, amplification of a proto-oncogene, and point mutation in a proto-oncogene," (Campbell 369). Most cancerous cells are found to contain chromosomes that have broken/rejoined incorrectly where fragments from one chromosome are located to another. "A proto-oncogene ending up in the joint region may now lie adjacent to an especially active promoter (or other control element) that increases transcription of the gene, making it an oncogene," (Campbell 369).
ReplyDeleteAssuming the ABL kinase signals the induction of apoptosis (is there verification? - online journals state that the main function of ABL is unknown) and controls the cell-cycle, the disruption of the ABL kinase would create unsuppressed growth. The ABL kinase would then be considered a tumor-suppressor because it would help prevent uncontrolled cell growth, "Any mutation that decreases the normal activity of a tumor-suppressor protein may contribute to the onset of cancer, in effect stimulating growth through the absence of suppression," (Campbell 369). If the protein that inhibits the cell cycle is denatured or not present, the growth-stimulating pathway and cell cycle of a cell will increase uncontrollably and if the cell continuously survives through many divisions - cancer has begun. Thus there is no negative feedback loop present - just one flow with no control.
CML cells become resistant to Gleevec cells through the "natural selection" mechanism. The "fittest" cells are those that can survive the Gleevec's toxin - thus those that carry a mutation, such as that of the C-to-T mutation in the ABL gene to cause a replacement of a threonine with an isoleucine, can change the active site of the ABL kinase. With the conformation of the active site changed, the Gleevec cannot act as a substrate to target the ABL kinase and it becomes ineffective. Eventually these CML cells with the mutation will survive and reproduce - allowing resistance to the Gleevec drug. A combination of drugs should be used in order to combat CML cells. With two drugs, the averages for mutations to occur to create resistance are decrease substantially. Another method could be to "hit hard and strong" the first time in order to "have the best chance of a complete and lasting cure," (Carroll 185).
For further reading material:
http://cancerres.aacrjournals.org/cgi/content/full/66/11/5648
http://jkweb.mcb.berkeley.edu/external/research-in-progress/5-3/signaling/abl_kinase.html
Thank you for the PNAS article:
ReplyDeletehttp://www.pnas.org/content/94/4/1437.full
...to confirm that apoptosis may be controlled by the ABL kinase. Thank you again.