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Intracellular Proadrenomedullin-Derived Peptides Decorate the Microtubules and Contribute to Cytoskeleton Function

Laboratory of Integrative and Medical Biophysics (D.L.S.), National Institute of Child Health and Human Development, and Cell and Cancer Biology Branch (L.O.), National Cancer Institute, Bethesda, Maryland 20892; Angiogenesis Core Facility (E.Z., F.C.), National Cancer Institute, Gaithersburg, Maryland 20877; Department of Medicine (L.W., J.M.C.), University of Virginia, Charlottesville, Virginia 22908; and Department of Cellular, Molecular, and Developmental Neurobiology (A.M.), Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain

Address all correspondence and requests for reprints to: Alfredo Martínez, Ph.D., Department of Cellular, Molecular, and Developmental Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain. E-mail: amartinez{at}cajal.csic.es.

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are secretory hormones, but it is not unusual to find them in intracellular compartments. Using yeast-2 hybrid technology, we found interactions between AM and several microtubule-associated proteins (MAPs), and between PAMP and tubulin. Expression of fluorescent-tagged AM and PAMP as well as immunofluorescence for the native peptides showed a complete decoration of the microtubules and colocalization with other MAPs. PAMP, but not AM, bound to tubulin in vitro and destabilized tubulin polymerization. Down-regulation of the gene coding for both AM and PAMP through small interfering RNA technology resulted in morphological changes, microtubule stabilization, increase in posttranslational modifications of tubulin such as acetylation and detyrosination, reduction in cell motility, and partial arrest at the G2 phase of the cell cycle, when compared with cells transfected with the same vector carrying a scrambled sequence. These results show that PAMP is a novel MAP, whereas AM may be exerting more subtle effects in regulating cytoskeleton function.