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    Researchers map out mutations in adrenal tumors that lead to Cushing’s syndrome

    12/04/2014

    The mutation of a key enzyme results in the secretion of abnormally high levels of cortisol in the adrenal gland. A group of researchers led by Martin Lohse and Davide Calebiro from the Rudolf Virchow Center at the University of Würzburg have now succeeded in mapping out the precise mechanisms. They report on this in the online journal “Nature Communications”.

    Cortisol is a hormone produced by the adrenal gland. It is regarded as a stress hormone and, in humans, it fulfils many vital functions. “Cortisol plays a number of important roles in metabolism,” says hormone researcher Davide Calebiro. However, too much cortisol – caused by the secretion of abnormally high levels – can lead, among other things, to diabetes, high blood pressure, and osteoporosis.

    These side-effects are grouped together by medics under the term “Cushing’s syndrome”, named for the person who first described it, Harvey Williams Cushing. Patients also put on weight and frequently develop depression. Without treatment, the mortality rate is raised significantly. The cause of the disorder tends to be tumors in the control center, the pituitary gland, or the adrenal gland.

    Mutation only recently recognized as a cause

    Over a third of patients affected with adrenal gland tumors are known to have a mutation in the gene for protein kinase A, a key enzyme for controlling hormone production in the adrenal glands. “But we still had no clear understanding of the precise mechanism that led to this increased enzyme activity,” says Calebiro.

    The actual role of the mutation was only recently identified as well, likewise by a research group with Würzburg involvement: Martin Fassnacht and Bruno Allolio from the Department of Medicine I at Würzburg University Hospital were leading members.

    The activating part of the enzyme complex is affected by mutation

    Calebiro, Fassnacht, and their colleagues have now managed to decipher this mutation. “During the initial structural biology studies signs soon emerged that the mutation mainly affects an important part of the ‘catalytic’, i.e. activating, subunit of the enzyme complex,” says Calebiro, whose work has now been published in the journal “Nature Communications”.

    Specifically, it appears as though the mutation intervenes in the formation of the complex. “Picture this as a combination of a key and a lock. If you change either of them, the mechanism will no longer work,” explains Calebiro.

    A balanced entity cannot be created as the “regulatory” subunit can no longer bind and inhibit the “catalytic” subunit. The complex cannot therefore be controlled by the signaling molecule cAMP. The activating subunit takes command, and cortisol is secreted unchecked.

    Possible approaches for treating Cushing’s syndrome

    Calebiro and his colleagues hope that better understanding of the genetic and molecular processes will lead to new approaches in the treatment of Cushing’s syndrome. “This knowledge has revealed to us a variety of potential targets for intervention,” says Calebiro, whose collaboration with Martin Fassnacht is funded by the University of Würzburg’s Interdisciplinary Center for Clinical Research (IZKF).

    The possibilities include creating molecules that dock directly onto the mutated “catalytic” subunit of protein kinase A and inhibit it in that way. Calebiro also sees value in working out in more detail what role the mutations play in other diseases as well.

    “PKA catalytic subunit mutations in adrenocortical Cushing’s adenoma impair association with the regulatory subunit” by Davide Calebiro, Annette Hannawacker, Sandra Lyga, Kerstin Bathon, Ulrike Zabel, Cristina Ronchi, Felix Beuschlein, Martin Reincke, Kristina Lorenz, Bruno Allolio, Caroline Kisker, Martin Fassnacht & Martin J. Lohse. DOI: 10.1038/ncomms6680 in Nature Communications, www.nature.com/naturecommunications 

    Contact

    Davide Calebiro, Institute of Pharmacology and Toxicology
    & Bio-Imaging Center/Rudolf Virchow Center

    M.: davide.calebiro@toxi.uni-wuerzburg.de, T.: +49 (0) 931 31 80067


    By Marco Bosch

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