10.12. Regulation of hyaluronan synthesis by UDP-sugars

Public examination of a doctoral dissertation in the field of Cell Biology

Doctoral candidate: MSc Tiina Jokela

Time and venue: 10.12. 2011 at 12 noon, Snellmania L21, Kuopio Campus

Language of the public examination: English

Language of the dissertation: Finnish

Hyaluronan is a large glycosaminoglycan comprised of alternating N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) units. Hyaluronan is synthesized by hyaluronan synthase enzymes (HAS1,2,3). In many tissues hyaluronan is a major component of the extracellular matrix. It enhances cell proliferation, migration, and controls differentiation. High hyaluronan levels are associated with cancer progression and inflammation.

In this study a new inhibitor of the hyaluronan synthesis, mannose, was discovered and it was demonstrated that it depletes content of UDP-GlcNAc. The three HAS enzymes showed different sensitivities to the cellular content of the UDP-GlcNAc.HAS3 had the highest affinity to the precursors and HAS1 the lowest, suggesting that the HAS-isoenzyme distribution in a particular cell type determines the sensitivity of its hyaluronan synthesis to UDP-sugar supply. Interestingly, a feedback mechanism from UDP-sugar content to HAS2 expression was found since fluctuations in UDP-GlcNAc content caused reciprocal changes in HAS2 transcription. This regulation is likely mediated by O-GlcNAc modifications of transcription factors YY1 and SP1.

This study also showed that hyaluronan-dependent binding of leukocytes can be induced by the inflammatory mediators and cell stress, and inhibited with mannose. In an in vivo wound model mannose reduced hyaluronan level, granulation tissue growth and accumulation of leukocytes.

Altogether, this work showed that cellular UDP-sugar content regulates hyaluronan synthesis and hyaluronan-mediated functions, like cell migration, proliferation, and leukocyte adhesion. Therefore, inhibition of hyaluronan synthesis by reduction of UDP-GlcNAc using mannose or similar effectors may provide novel ways to treat pathological processes that involve excessive hyaluronan production, e.g. in inflammation and cancer.

The doctoral dissertation of Master of Science Tiina Jokela, entitled Regulation of hyaluronan synthesis by UDP-sugars will be examined at the Faculty of Haelth Sciences. The opponent in the public examination will be  Professor Jens W. Fischer of Heinrich-Heine-Universität Düsseldorf,  and the custos will be Professor Markku Tammi of the University of Eastern Finland. The public examination will be held in English.

Photo available for download at http://www.uef.fi/vaitoskuvat

For further information, please contact: Tiina Jokela, p. 044-5254308, tiina.jokela@uef.fi

Publishing year: 2011

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