Nature Cell Biology: The Jiang Hao team revealed that AKAP95 can regulate gene splicing and tumor generation through phase separation.

Cancer !---- is often associated with gene expression disorders, including regulatory abnormalities at the levels of chromosomes, transcription, mRNA splicing, etc.like a chemical reaction within all cells, gene expression is not evenly distributed within the nucleus, but is separated in space-time (aralized) to be properly carried out and regulated.in addition to the membrane structure of the organ, another type of membraneless organiser is also an important separation method.recent years have shown that liquid-liquid phase separation is the fundamental driving force behind the formation of so-called biomolecular condensers and many non-nuclear cells.with different biological processes, these condensers have a range of different biophysical properties, from highly dynamic molecules to semifluids or glis to fiber and solid states with poor molecular activity, including chromosomes, transcriptions, and mRNA splicing molecules that form condensate and active.However, it is not known how different biophysical properties of the condensate affect gene expression and cancer.July 27, 2020, the University of Virginia's Jiang Hao team published an article in the journal Nature Cell Biology, Biophysical Propertyies of AKAP95 Protein Condensates Regulate splicing and tumorigenesis, revealing that the nucleus protein KAP95 regulates gene spruns and tumor generation through liquid phase separation within the range of appropriate condensed body biophysical properties.previous studies have found that the nucleus protein AKAP95 regulates gene expression, especially mRNA splicing.in the study, they found that AKAP95 directly regulates mRNA splicing of some cancer genes to support the growth of cancer cells.mice had no effect on their development or physiology when they were knocked out of the Akap95 gene.the mice's embryonic fibroblasts grow normally, but it is difficult to be converted into cancer cells, and enters cell aging when the cancer gene is active, accompanied by mRNA shearing abnormalities.So AKAP95 may be a potential cancer treatment target.they then study the molecular mechanism of the protein's regulatory shear., due to the unusual self-binding ability of the protein under denaturation conditions, AKAP95 was found to form liquid particles in vitro by phase separation and highly dynamic condensers in the nucleus.mutates tyrosine (Tyr) in an internal disordered region (IDR) into alanine or seranine (Seraine) to completely lose the ability to split phases and make it lose the ability to cut and regulate.replace its own IDR with a phase-separation ability from unrelated proteins to maintain its ability to separate phases and shear regulation.these results support AKAP95 need phase separation capability to regulate shear. interesting is the IDR's tyrosine mutation into a control of phenylalanine (Phe) (because both amino acids have aromatic rings). the mutant also forms a condensate, but its ability to cut and regulate has decreased significantly. this caught the author's attention. careful quantitative study, they found that the mutant was more phase-divided, that the condensate formed in vitro and intracellular was more solid than liquid, and that the molecular activity and diffusion coefficient of the condensed body decreased significantly (in collaboration with the UCI Gratton team). this mutation reduces the molecular motion and collision in the shear reaction, thus reducing the efficiency of the shear reaction. they eventually returned to the human and mouse cell systems to check the regulation of AKAP95 phase separation on cancer cells and endogenous gene splicing. they found that the mutants that lost the ability to isolate phasecomplete completely lost the ability to support the growth of cancer cells and inhibit their ability to slicing the endogenous gene, and the mutations that cured the condensed body significantly reduced all of these abilities. in all, the study revealed that some gene-regulating proteins, such as AKAP95, not only need to separate to form condensate, but also need to have good activity to regulate gene expression and cancer within the range of a suitable coagulation biophysical properties. this also provides an unconventional idea for cancer treatment--- may be able to suppress cancer cells by intervening (chemicalized or hardening) in both directions of the coagulation properties. .