Importance of Rce1 and Ras in tobacco-induced cancers
Abstracts
Initial Award Abstract |
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One of the most devastating tobacco-related diseases is lung cancer. In normal cells and tissues, Ras proteins are responsible for transmitting signals for cell division and growth. In many lung cancers, it is possible to detect an activating mutation in one of the Ras proteins. Specific mutations in the Ras proteins can activate this signaling process, resulting in continuous and uncontrolled filled cell division. This uncontrolled cellular growth is one of the steps in the development of cancer.
The Ras proteins undergo three different processing events that are crucial for the proper localization and function of these proteins within the cell. The first step, the attachment of a lipid (a type of fat molecule) to these proteins, has been shown to be extremely important for Ras function. One class of drugs inhibits the addition of a specific lipid to Ras proteins and has been shown to retard the growth of cancers in animal models. However, some recent observations suggest that these drugs may not be effective in preventing the growth of all Ras-induced cancers.
The second processing step involves the removal of the last three amino acids from the Ras proteins. Our laboratory has been studying a mouse gene, Rce1, which is involved in that processing step. Our laboratory has generated mice that lack the Rce1 gene, from which we have cultured cells that lack Rce1 and demonstrated that Ras processing is blocked in those cells. Also, we found that the Ras proteins are not properly localized within cells lacking Rce1. We have hypothesized that the abnormal location of the Ras proteins within cells may prevent their normal function. If this is the case, blocking Rce1 function might prove to be a very reasonable target for anticancer drug therapy.
During my fellowship, I will determine whether the blockade of Rce1 function is a reasonable target for treating Ras-induced cancers. The first aim of this proposal is to fully characterize liver-specific Rce1 function in an animal model. The second aim will be to assess the role of Rce1 in a normal cellular proliferation event; i.e., liver regeneration, which is thought to depend on the Ras signaling pathway. The third aim will be to compare the growth of Ras-induced cancers in nice with normal Rce1 expression and in mice that lack Rce1 gene expression in specific tissues. It will be very interesting to determine if smaller and/or fewer tumors are produced in the absence of Rce1. If cancer growth is retarded in the absence of Rce1, then blocking this pathway might be a useful strategy for retarding the growth of Ras-induced cancers in humans. This work is highly relevant to tobacco-related disease, since many human lung cancers have activating mutations in one of the Ras proteins. |
Final Report |
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One of the most devastating tobacco-related diseases is lung cancer. Ras proteins transmit signals for cell division and growth. In many human cancers, specific mutations in Ras proteins activate this signaling process, resulting in continuous and uncontrolled cell division. This uncontrolled cellular growth is one of the steps in the development of cancer. Several processing events are crucial for their proper intracellular localization and function. First, attachment of a lipid to the protein is extremely important for Ras function. One class of drugs that inhibit the addition of one of the lipids retards the growth of cancers in animal models. The second processing step involves the removal of the last three amino acids from the Ras proteins. Our laboratory has been studying the mouse gene, Rce1 that is involved in this step. We have generated mice that lack the Rce1 gene. Unfortunately, these mice died before being born. However, we have cultured cells from embryos that lack Rce1 and have demonstrated that normal Ras processing is blocked in those cells and that the Ras proteins are not properly localized in the cell. We hypothesized that the abnormal location of the Ras proteins within cells should prevent normal Ras function. If this is the case, blocking Rce1 function might prove to be a reasonable target for anticancer drug therapy.
In my initial fellowship application, I proposed determining whether the blockade of Rce1 function is a reasonable target for interfering with cell growth. The first aim of my grant was to produce and characterize mice that lack Rce1 in the liver. I have completed this aim; I have generated liver-specific Rce1 knockout mice using two different experimental techniques. The mice are healthy and have no obvious liver dysfunction. The second aim was to assess the role of Rce1 in noncancerous cellular proliferation. Within this aim, I proposed to test whether the absence of liver Rce1 expression in the liver-specific Rce1 knockout mice affects liver regeneration after surgical removal of most of the liver (partial hepatectomy). I have completed two series of experiments. The first appeared to be informative. I performed hepatectomies on mice in which ~80% of the liver cells lacked Rce1. Interestingly, all of the liver regeneration in those animals appeared to stem from the ~20% of cells that expressed Rce1 (and not from the ~80% of cells that lacked Rce1), strongly suggesting that Rce1 expression is critical for this normal cellular proliferation event. The third specific aim was to compare the growth of Ras-induced cancers in tissues with normal Rce1 expression and in tissues that lack Rce1 expression, using tissue-specific Rce1 knockout mice. During the past year, I have been successful in gaining insights into the functional importance of Rce1 in governing cell growth and the growth of Ras induced cancers. I have submitted a manuscript on that to Molecular and Cellular Biology, and it has been accepted, contingent on the completion of one experiment (an experiment that I recently completed!).
This research is highly relevant to tobacco-related disease, since many human lung cancers involve activating mutations in the Ras proteins. |
Publications
| Targeted inactivation of the isoprenylcysstein carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Bergo MO, Leung GK, Ambroziak P, Otto JC, Casey PJ, Young SG |
ART |
| Yr: 2000 |
Vol: 275 |
Nbr: |
Abs: |
Pg: 17605-17610 |
| Domain and methylation of K-Ras are critical for the interaction between K-Ras and microtubules |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Chen Z, Otto JC, Bergo MO, Young SG, Casey PJ |
ART |
| Yr: 2000 |
Vol: 275 |
Nbr: |
Abs: |
Pg: 41251-41257 |
| Isoprenylcysteine carboxyl methyltransferase deficiency in mice |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Bergo MO, Leung GK, Ambroziak P, Gomes AR, Seabra MC, Young SG |
ART |
| Yr: 2000 |
Vol: 276 |
Nbr: |
Abs: |
Pg: 5841-5845 |
| Biochemical studies of Zmpste24-deficient mice |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Leung GK, Schmidt WK, Bergo MO, et al |
ART |
| Yr: 0 |
Vol: |
Nbr: |
Abs: |
Pg: |
| Targeted inactivation of the isoprenylcysstein carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Bergo MO, Leung GK, Ambroziak P, Otto JC, Casey PJ, Young SG |
ART |
| Yr: 2000 |
Vol: 275 |
Nbr: |
Abs: |
Pg: 17605-17610 |
| Domain and methylation of K-Ras are critical for the interaction between K-Ras and microtubules |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Chen Z, Otto JC, Bergo MO, Young SG, Casey PJ |
ART |
| Yr: 2000 |
Vol: 275 |
Nbr: |
Abs: |
Pg: 41251-41257 |
| Isoprenylcysteine carboxyl methyltransferase deficiency in mice |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Bergo MO, Leung GK, Ambroziak P, Gomes AR, Seabra MC, Young SG |
ART |
| Yr: 2000 |
Vol: 276 |
Nbr: |
Abs: |
Pg: 5841-5845 |
| Biochemical studies of Zmpste24-deficient mice |
| Periodical: Journal of Biological Chemistry |
Index Medicus: |
| Authors: Leung GK, Schmidt WK, Bergo MO, et al |
ART |
| Yr: 0 |
Vol: |
Nbr: |
Abs: |
Pg: |
