The regulation of interferon signaling and ER stress response by different Akt isoforms.
Abstract: The protein
kinases Akt1, Akt2, and Akt3 possess non-redundant signaling properties, few of which
have been investigated. Here we present evidence for an Akt1-dependent pathway that
controls interferon-regulated gene expression and antiviral immunity. The target of this
pathway is EMSY, an oncogenic interacting partner of BRCA2 that functions as a
transcriptional repressor. Overexpression ... read moreof EMSY in hTERT-immortalized mammary
epithelial cells, and in breast and ovarian carcinoma cell lines, represses
interferon-stimulated genes (ISGs) in a BRCA2-dependent manner, while its knockdown has
the opposite effect. EMSY binds to the promoters of ISGs, suggesting that EMSY functions
as a direct transcriptional repressor. Akt1, but not Akt2, phosphorylates EMSY at
Ser209, relieving EMSY-mediated ISG repression. The Akt1/EMSY/ISG pathway is activated
by both viral infection and interferon and inhibits the replication of Herpes Simplex
Virus 1 type 1 (HSV-1) and Vesicular Stomatitis Virus (VSV). Collectively, these data
define an Akt1-dependent pathway which contributes to the full activation of ISGs by
relieving their repression by EMSY and BRCA2.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Biochemistry.
Advisor: Philip Tsichlis.
Committee: Philip Hinds, Brian Schaffhausen, Alexei Degterev, and Karl Munger.
Keyword: Biochemistry.read less