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2018 ; 41
(6
): 3211-3220
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hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic
effects through suppression of TGF?? signaling
#MMPMID29568955
Chen W
; Shin KH
; Kim S
; Shon WJ
; Kim RH
; Park NH
; Kang MK
Int J Mol Med
2018[Jun]; 41
(6
): 3211-3220
PMID29568955
show ga
GV1001 is a 16?amino acid peptide derived from the human telomerase reverse
transcriptase (hTERT) protein (616?626; EARPALLTSRLRFIPK), which lies within the
reverse transcriptase domain. Originally developed as an anticancer vaccine,
GV1001 demonstrates diverse cellular effects, including anti?inflammatory, tumor
suppressive and antiviral effects. In the present study, the radioprotective and
antifibrotic effects of GV1001 were demonstrated through suppressing transforming
growth factor?? (TGF??) signaling. Proliferating human keratinocytes underwent
premature senescence upon exposure to ionizing radiation (IR), however, treatment
of cells with GV1001 allowed the cells to proliferate and showed a reduction in
senescent phenotype. GV1001 treatment notably increased the levels of
Grainyhead?like 2 and phosphorylated (p?)Akt (Ser473), and reduced the activation
of p53 and the level of p21/WAF1 in irradiated keratinocytes. It also markedly
suppressed the level of TGF?? signaling molecules, including p?small mothers
against decapentaplegic (Smad)2/3 and Smad4, and TGF?? target genes, including
zinc finger E?box binding homeobox 1, fibronectin, N?cadharin and Snail, in
irradiated keratinocytes. Furthermore, GV1001 suppressed TGF?? signaling in
primary human fibroblasts and inhibited myofibroblast differentiation. Chromatin
immunoprecipitation revealed that GV1001 suppressed the binding of Smad2 on the
promoter regions of collagen type III ?1 chain (Col3a1) and Col1a1. In a dermal
fibrosis model in vivo, GV1001 treatment notably reduced the thickness of
fibrotic lesions and the synthesis of Col3a1. These data indicated that GV1001
ameliorated the IR?induced senescence phenotype and tissue fibrosis by inhibiting
TGF?? signaling and may have therapeutic effects on radiation?induced tissue
damage.