The scientists from the Western Australian Institute for Medical Research in Perth, have identified a gene - RGS5 which makes a signalling molecule that can reverse angiogenesis - the growth of blood vessels inside a tumour.
It is the uncontrolled growth of blood vessels and the formation of abnormal blood vessels inside tumours that 'feed' them, allowing them to grow and stops the immune system from attacking them.
Many cancer therapies currently in use target the blood vessels in tumours, which are thought to feed the cancer cells.
Associate professor Dr. Ruth Ganss who led the research team says by modulating the blood vessels within the tumour, the whole tumour environment can be changed which makes it more susceptible to treatment.
Dr. Ganss says this offers an alternative to just killing the blood vessels with the cancer therapy.
For the research the scientists used genetically-altered mice which developed pancreatic cancer and half of them had the RGS5 gene missing.
Dr. Ganss says the tumours grew in both groups of mice, but the blood vessels looked very chaotic and abnormal in the mice which had the gene and looked normal when the gene was missing.
For the next step the researchers injected anti-cancer cells into both groups of mice and it was found that the mice without the gene were much more responsive to treatment and lived longer.
The researchers say the anti-cancer cells went directly into the tumour, the tumour shrank, there was less tumour burden and the mice survived longer.
In the group of mice with the gene the anti-cancer cells did not reach the tumour in sufficient numbers to have any impact on the tumour.
The result meant the mice without the gene lived at least 10 weeks longer and researchers found their tumours were half the size.
Dr. Ganss says the research shows that RGS5 is a master gene in angiogenesis and when it is removed, angiogenesis reverses and the blood vessels in tumours appear more normal.
The team say the protein, RGS5 could well be a target for anti-cancer therapy, however while the finding could help improve cancer therapy, it does not represent in any way a cure.
The research is published in the journal Nature.
In their latest search for detail, Maquat and colleagues determined that the delivery of a given faulty mRNA to the degradation machinery requires first the active shutdown (translational repression) of protein building based on that mRNA. In the study ™s key finding, experiments revealed that repression of protein synthesis during NMD is controlled the attachment of phosphate groups to human UPF1, researchers said. Human cells have evolved such that phosphorylation, the attachment of phosphate groups to proteins, is used in many scenarios like a switch to turn processes on or off.
Based on their findings, Maquat and colleagues propose the following new model for NMD: When a nonsense stop codon is detected, UPF1 together with the enzyme that directs its phosphorylation interacts with the EJC. The same step makes possible the attachment of phosphate groups to UPF1. Once phosphorylated, UPF1 interacts directly with and inhibits the function of eukaryotic initiation factor 3 (eIF3), which would otherwise direct protein building based on that mRNA sequence.
Normally, eIF3 drives a key change in a complex (40S/Met-tRNAiMet/mRNA) that consists of mRNA and part of a functional ribosome. The binding of phosphorylated UPF1 to eIF3 prevents this complex from going on to form a complex (80S/Met-tRNAiMet/mRNA) that consists of mRNA and the completed functional ribosome, and that is capable of driving translation.
The team corroborated the importance of eIF3 as a target for translational repression during NMD using an experiment with an mRNA sequence from cricket paralysis virus. Where human cells use eIF3 to initiate translation, the cricket virus mRNA sequence does not. Researchers found that the non-eIF3 translation initiation directed by the cricket virus sequence in mammalian cells was resistant to NMD, and thus that eIF3 is a must for the translational repression that makes NMD possible.
In Maquat ™s model of NMD, phospho-UPF1 not only inhibits the pioneer round of translation so that the translational machinery "falls away" from the flawed mRNA at hand, but also recruits degradative enzymes to that mRNA.
Along with Maquat, the study was authored by post-doctoral associates Olaf Isken, Yoon Ki Kim and Nao Hosoda under the auspices of the Medical Center. Greg L. Mayeur and John W.B. Hershey from the Department of Biological Chemistry at the University of California at Davis provided important reagents and advice. This work was supported by the National Institutes of Health.
Our study provides the first evidence that translational repression does indeed occur during NMD in mammalian cells, Maquat said. One implication of these results is that we have a new target by which the decay of faulty mRNA can be prevented. In cases where a nonsense codon occurs in a gene supplying an essential protein, and thus causes disease via protein shortage, we may be able to design drugs that suppress related decay. That could restore the supply of an mRNA that can direct the cell to synthesize full-length, functional proteins.
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