The Axin1 scaffold protein promotes formation of a degradation complex for c‐Myc

HK Arnold, X Zhang, CJ Daniel, D Tibbitts… - The EMBO …, 2009 - embopress.org
HK Arnold, X Zhang, CJ Daniel, D Tibbitts, J Escamilla‐Powers, A Farrell, S Tokarz…
The EMBO journal, 2009embopress.org
Expression of the c‐Myc proto‐oncoprotein is tightly regulated in normal cells.
Phosphorylation at two conserved residues, threonine58 (T58) and serine62 (S62),
regulates c‐Myc protein stability. In cancer cells, c‐Myc can become aberrantly stabilized
associated with altered T58 and S62 phosphorylation. A complex signalling cascade
involving GSK3β kinase, the Pin1 prolyl isomerase, and the PP2A‐B56α phosphatase
controls phosphorylation at these sites. We report here a novel role for the tumour …
Expression of the c‐Myc proto‐oncoprotein is tightly regulated in normal cells. Phosphorylation at two conserved residues, threonine58 (T58) and serine62 (S62), regulates c‐Myc protein stability. In cancer cells, c‐Myc can become aberrantly stabilized associated with altered T58 and S62 phosphorylation. A complex signalling cascade involving GSK3β kinase, the Pin1 prolyl isomerase, and the PP2A‐B56α phosphatase controls phosphorylation at these sites. We report here a novel role for the tumour suppressor scaffold protein Axin1 in facilitating the formation of a degradation complex for c‐Myc containing GSK3β, Pin1, and PP2A‐B56α. Although knockdown of Axin1 decreases the association of c‐Myc with these proteins, reduces T58 and enhances S62 phosphorylation, and increases c‐Myc stability, acute expression of Axin1 reduces c‐Myc levels and suppresses c‐Myc transcriptional activity. Moreover, the regulation of c‐Myc by Axin1 is impaired in several tested cancer cell lines with known stabilization of c‐Myc or loss of Axin1. This study provides critical insight into the regulation of c‐Myc expression, how this can be disrupted in three cancer types, and adds to our knowledge of the tumour suppressor activity of Axin1.
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