Cyclin dependent-kinases (Cdks) promote cell cycle progression. Cyclin-dependent kinase inhibitor 1B (p27kip1) plays a critical role in negatively controlling cell cycle progression at G1 phase by inhibiting cyclin E-Cdk2 and cyclin D-Cdk4. It is a tumor suppressor protein commonly deregulated in aggressive human cancers. The mechanisms by which this deregulation occurs remain incompletely described, making it difficult to design targeted therapies. The enzyme transglutaminase (TG) catalyzes formation of a covalent bond between a free amino group and the acyl group in glutamine. It typically generates intermolecular crosslinks between lysine and glutamine residues on different polypeptide chains, thereby covalently linking two or more protein monomers. Microbial transglutaminase (mTG) is widely used as meat glue to produce foods such as imitation crabmeat and chicken nuggets. Mammalian TGs play important roles in blood clotting, wound healing and skin organization. Tissue transglutaminase (tTG or TG2) is considered to be the most versatile mammalian TG because of its participation in multiple biological processes. TG2 expression increases in some types of cancer, which may contribute to cellular transformation. We found that both mTG and human TG2 utilize human wild type p27 as a substrate, but in a novel manner. Rather than covalently linking p27 monomers, TG catalyzed intramolecular bond formation between a glutamine and lysine on the same p27 protein. This modification generated a more compact p27 as indicated by its faster migration on a polyacrylamide gel. Most importantly, TG modification of p27 structure altered its function, preventing its binding to Grb2 complexes. On the other hand, cyclin E can bind to both the unmodified and modified p27. These results suggest TG modification of p27 may be a novel regulatory mechanism affecting its tumor suppressing function.

Novel regulation of tumor suppressor P27kip1 by transglutaminase

251st National Meeting (2016)

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