Inactivation Of Methylating Enzyme Inhibits Oncogene-Mediated Tumor Formation
NEW YORK (Reuters Health) - Inactivation of the gene encoding the methyltransferase Icmt inhibits transformation of cells by oncogenes K-Ras and B-Raf, researchers report. While the research is in early stages, "The experiments we have underway will determine whether inhibition of Icmt will prevent malignant cell growth in an in vivo setting," according to the lead investigator.
Icmt deficiency results in mislocalization of Ras proteins within cells, the authors explain, but little is known about the effects of Icmt deficiency on cell growth and oncogenic transformation.
Dr. Martin O. Bergo from Gladstone Institute of Cardiovascular Disease, San Francisco, California and colleagues generated fibroblast cell lines bearing a conditional Icmt allele and analyzed the consequences of inactivating Icmt.
Fibroblasts with inactivated Icmt showed 40% to 60% reduced cell growth, the authors report in the February issue of The Journal of Clinical Investigation, and Icmt inactivation slowed the growth of hepatocytes in mice.
Inactivation of Icmt markedly inhibited the ability of K-Ras-transformed cells to grow in soft agar and in nude mice, the results indicate, and blocked B-Raf-induced transformation of fibroblasts.]
Icmt inactivation produced a large increase in the levels of the regulatory protein p21(Cip1), the researchers note, but knocking out p21(Cip1) restored the capacity of Icmt-deficient K-Ras-transformed cells to grow in soft agar.
"(This) suggests that Icmt knock-out mediated inhibition of cell growth and K-Ras transformation requires p21(Cip1)," the investigators write.]
"I am setting up a lab at Sahlgrenska University Hospital in Gothenburg, Sweden," Dr. Bergo told Reuters Health. "My first goal will be to use a novel genetic approach in vivo to activate an oncogenic form of K-ras and simultaneously inactivate Icmt in a tissue specific manner. We (and others) found that turning on the expression of this oncogenic form of K-Ras in hematopoietic cells with the Mx1-Cre transgene results in a rapidly progressing and lethal myeloproliferative disease (MPD). Now, it will be very interesting to see if the simultaneous inactivation of Icmt can block this MPD."
As for the therapeutic implications, "It is too early to say whether Icmt inhibitors will be seen in a clinical setting, but the current research provides encouragement that they may be useful to block the growth of the many human malignancies that harbor mutations in K-Ras and B-Raf," Dr. Bergo concluded.
Given these results, "it now appears worthwhile to resume the search for more effective inhibitors of the Icmt-encoded methyltransferase that may mimic the antiproliferative effect of the knockout of this enzyme in mice," write Dr. Steven Clarke and Dr. Fuyuhiko Tamanoi from University of California, Los Angeles, California in a related editorial.
"Because the Icmt enzyme is one of a relatively small class of methyltransferases characterized by multiple membrane-spanning segments, it may be possible to develop a new class of inhibitors that take advantage of this particular structure."
Source: J Clin Invest 2004;113:539-550,513-515. [ Google search on this article ]