Pharmacological manipulation of the Akt signaling pathway regulates myxoma virus replication and tropism in human cancer cells

Steven J. Werden, Douglas McFadden

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Viruses have evolved an assortment of mechanisms for regulating the Akt signaling pathway to establish a cellular environment more favorable for viral replication. Myxoma virus (MYXV) is a rabbit-specific poxvirus that encodes many immunomodulatory factors, including an ankyrin repeat-containing host range protein termed M-T5 that functions to regulate tropism of MYXV for rabbit lymphocytes and certain human cancer cells. MYXV permissiveness in these human cancer cells is dependent upon the direct interaction between M-T5 and Akt, which has been shown to induce the kinase activity of Akt. In this study, an array of compounds that selectively manipulate Akt signaling was screened and we show that only a subset of Akt inhibitors significantly decreased the ability of MYXV to replicate in previously permissive human cancer cells. Furthermore, reduced viral replication efficiency was correlated with lower levels of phosphorylated Akt. In contrast, the PP2A-specific phosphatase inhibitor okadaic acid promoted increased Akt kinase activation and rescued MYXV replication in human cancer cells that did not previously support viral replication. Finally, phosphorylation of Akt at residue Thr308 was shown to dictate the physical interaction between Akt and M-T5, which then leads to phosphorylation of Ser473 and permits productive MYXV replication in these human cancer cells. The results of this study further characterize the mechanism by which M-T5 exploits the Akt signaling cascade and affirms this interaction as a major tropism determinant that regulates the replication efficiency of MYXV in human cancer cells.

Original languageEnglish (US)
Pages (from-to)3287-3302
Number of pages16
JournalJournal of Virology
Volume84
Issue number7
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Fingerprint

Myxoma virus
tropisms
Tropism
Virus Replication
virus replication
Pharmacology
Neoplasms
phosphorylation
phosphotransferases (kinases)
Phosphotransferases
rabbits
Poxviridae
Phosphorylation
Permissiveness
Ankyrin Repeat
ankyrins
Rabbits
Efficiency
okadaic acid
Okadaic Acid

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Pharmacological manipulation of the Akt signaling pathway regulates myxoma virus replication and tropism in human cancer cells. / Werden, Steven J.; McFadden, Douglas.

In: Journal of Virology, Vol. 84, No. 7, 01.04.2010, p. 3287-3302.

Research output: Contribution to journalArticle

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