The first UPR gene to show up-regulation was
Bip at P15.
Bip is a molecular chaperone that recognizes misfolded proteins. Its expression was increased ∼ 1.5-fold compared to the wild-type (control) at P15 (
P < 0.0001,
Fig. 2,
Supplementary Table S1). However, at P18 and P21, no significant difference in
Bip expression was observed.
Bip expression was elevated significantly again at P25 (an increase of 1.5-fold compared to the control,
P < 0.01). Other chaperones, such as
Calnexin (
Cnx) and
Hsp90B1, also showed increased expression (
Fig. 2,
Supplementary Table S1). Expression of
Cnx was increased in hT17M
Rho mice 1.3-, 1.3-, 1.6-, and 1.8-fold at P15, P18, P21, and P25, respectively (
P < 0.01,
P < 0.05,
P < 0.0001, and
P < 0.0001, respectively). Conversely,
Hsp90B1 was not significantly up-regulated after P15 (1.4-fold increase,
P < 0.01). The
Eif2α gene also was significantly up-regulated at P15 and P18 (∼1.2- and ∼1.3-fold increase,
P < 0.05 and
P < 0.01, respectively).
Atf4 gene expression, another marker of the PERK pathway that is translated preferentially by phosphorylated Eif2α, was elevated significantly at P15, P18, and P21 (∼1.4-fold increase,
P < 0.05 for all time points) and then declined with time. Interestingly,
CHOP, which is a target of the ATF4 transcription factor, already was over-expressed at P12 (∼1.3-fold increase,
P < 0.01). Its expression at P15 was increased 1.5-fold (
P < 0.001). At this time point, expression of the
Eif2α and
Atf4 genes (PERK pathway) already was elevated.
Atf6 gene expression (ATF6 pathway) was modulated at all time points; however, it was not significantly different from that in the control.
Xbp1 gene expression (IRE1 pathway) was increased significantly from P15 (1.5-fold increase,
P < 0.0001) until P25.