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This version published online on March 6, 2008
Endocrinology, doi:10.1210/en.2007-1763
A more recent version of this article appeared on June 1, 2008
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Submitted on December 19, 2007
Accepted on February 25, 2008

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

Dan L. Sackett, Laurent Ozbun, Enrique Zudaire, Lisa Wessner, John M. Chirgwin, Frank Cuttitta, and Alfredo Martínez*

Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, Bethesda, MD 20892; Cell and Cancer Biology Branch, National Cancer Institute, Bethesda, MD 20892; Angiogenesis Core Facility, National Cancer Institute, Gaithersburg, MD 20877; Department of Medicine, University of Virginia, Charlottesville, VA 22908; and Department of Cellular, Molecular, and Developmental Neurobiology, Instituto Cajal, CSIC, 28002 Madrid, Spain

* To whom correspondence should be addressed. 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. Downregulation of the gene coding for both AM and PAMP through siRNA technology resulted in morphological changes, microtubule stabilization, increase in post-translational modifications of tubulin such as acetylation and de-tyrosination, reduction in cell motility, and partial arrest at the G2 phase of the cell cycle, when compared to 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.






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