22 August 2013

Cancer node

The development of cancer depends on the nodes in the mRNA

Kirill Stasevich, CompulentaThe synthesis of a polypeptide chain on a matrix RNA depends on a variety of serving proteins, which can be generally called "ribosomal pilots":

they show a huge ribosome machine where to sit on mRNA, where to start synthesis, etc.

And among these helper proteins there is one that has long been recognized as one of the strongest oncogenes. This is the eukaryotic translation initiation factor 4E (eIF4E), and, generally speaking, everything starts with it: it binds to a special structure at the "initial" end of the mRNA and tells other proteins where they need to prepare the ribosome landing site. At the same time, he binds to some mRNAs more often, and some, on the contrary, he does not like. Among those who are ignored, mRNAs encoding tumor signals often come across. In other words, if these mRNAs begin to be read too actively by ribosomes, the cell will become malignant.

But if 4E itself becomes a lot, it starts activating cancer mRNAs more often than it should. For the first time, the oncogenic property of 4E became known in 1978, and despite the fact that the translation process was literally disassembled during this time, no one could answer the question of what exactly 4E does with oncogenic mRNAs.

We managed to find out about it only now. Katerina Feoktistova and her colleagues at the University of California, Davis (USA) published an article in the journal PNAS (Human eIF4E promotes mRNA restructuring by stimulating eIF4A helicase activity), which describes the features of the interaction of helper protein 4E with another helper protein, 4A.

As you know, every mRNA has nodes, loops and other entanglements in its structure, which are formed due to mutually complementary sections of the molecule. On the other hand, when the ribosome is just beginning to assemble on mRNA, then first one of the ribosomal halves lands on the nucleic acid, which will have to "crawl" along the mRNA from the landing point to the beginning of the protein code, where it will unite with another ribosomal half and begin biosynthesis. (Recall that not all of the mRNA molecule carries a coding sequence: some regions are needed only for regulatory purposes and are not read into a protein.)

And if there are RNA nodes and RNA loops on the path of the ribosomal half, it cannot untangle them itself: for this it needs an assistant, protein 4A. It is he who takes the trouble to untangle the nucleic acid (with the expenditure of energy, of course), to clear, so to speak, the path of the ribosome. Then, when the whole ribosome travels through the RNA, it will be able to wade through such structural complications by itself, but until the ribosome has assembled, it needs help.

So, it turned out that the activity of the untangling 4A directly depends on the signal 4E. Interacting with 4A, signal 4E increases its activity, and 4A unravels, so to speak, better and more. And cancer mRNAs have just a lot of such obstacles in the way of the ribosomal half, and then there is too much work for the unraveling protein. Normally, some proportion of these mRNAs are still translated, after all, they encode the proteins needed by the cell. But if 4E becomes a lot, it not only focuses the attention of the entire translational machinery on such mRNAs, but also stimulates 4A to unravel these mRNAs as completely as possible. Further – a tumor.

In a normal cell (on the left), the cancer mRNA remains unopened in its "front" part, but in a cancer cell (on the right), due to an excess of protein 4E (red circles), it becomes readable by ribosomes, and the level of cancer proteins in the cell increases. (Drawing by Katerina Feoktistova / UC Davis.)The question arises why no one has known about this side of the relationship between 4A and 4E until now, although both proteins have been known to scientists since time immemorial (by the standards of molecular biology, of course).

But until now, these proteins could hardly separate one from the other and did not think too much about what 4A does without 4E. Protein 4E has long been studied as a potential target for anti–cancer drugs - well, now at least it is clear which feature of 4E developers of such drugs should pay special attention to.

Prepared based on the materials of Medical Xpress: How untying knots promotes cancer.

Portal "Eternal youth" http://vechnayamolodost.ru22.08.2013

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