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Transcriptional factors such as metal transcription factor-1 (MTF-1), p53, Sp1,
Sp-3, and cleaved activating transcription factor 6 α (ΔATF6α) and spliced X-box
protein-1 (sXBP1) have all been reported to increase PrP expression, whereas Yin
Yang-1 (YY1), nuclear factor-erythroid 2-related factor-2 (Nrf-2), and Hes-1
reduced PrP expression [ 8 – 13 ]. In addition to transcriptional regulation, about 70%
of rat brain PrP mRNA is associated with polysomes and thus is subject to transla-
tional regulation [ 14 ]. Whether PrP mRNA in other species has the same level of
polysome association remains to be investigated. More importantly, this association
implies that the cells may need a quick synthesis of PrP under certain conditions.
However, not much is known on this aspect. Contrary to translational regulation, a
lot has been learned for posttranslational modification of prion protein. The newly
synthesized human PrP protein is a 254 amino acid polypeptide with a N-terminal
leader peptide (amino acids 1–22) for the endoplasmic reticulum (ER) and a
C-terminal glycosylphosphatidylinositol (GPI) signaling sequence (GPI-PSS)
(amino acids 232–254). The N-terminal leader signal is cleaved upon entry into
ER. However, due to its low efficacy to guide PrP into ER, cytosolic PrP is detected
in many cell types [ 15 ]. It remains to be determined whether this cytosolic PrP is
pro-PrP or not. Similar to the inefficiency of the N-terminal signal, in vitro experi-
ment proved that the C-terminal GPI-PSS of PrP is of low efficiency in replacing
GPI anchor compared to other GPI-anchored proteins [ 16 ]. Besides N-terminal and
C-terminal signals, human PrP may also be modified with N-linked glycans on
N181 and N197 and intramolecular disulfide bond connecting C179 and C214. The
significance of N-linked glycans and intramolecular disulfide bonds remains eluci-
dated for the physiological function of PrP, although it is reported that intramolecu-
lar disulfide bonds are required for the alpha-helical conformation of recombinant
PrP [ 17 ]. Like other GPI-anchored proteins, PrP is tethered on the outer leaflet of
the cholesterol-enriched cell membrane domain called lipid raft by means of its GPI
anchor. Lipid raft is the platform to integrate cellular signaling, and some membrane
receptors have been shown recruited into lipid raft to be activated [ 18 , 19 ]. Although
the physiological functions of PrP in vivo remain unidentified, the location of PrP in
lipid raft implicates that PrP is involved in signal transduction or adhesion. By anti-
body crosslinking, it has been shown that PrP can activate tyrosine kinase Fyn in
murine 1C11 neuronal differentiation model [ 20 ]. Besides antibody crosslinking,
PrP can also stimulate signaling pathway by interacting with its physiological part-
ners. For example, when binding to stress-inducible protein 1, PrP may activate
mTOR [ 21 ], a pathway involved in cancer cell growth. PrP also plays roles in other
signaling pathways important for cancer cell growth, such as anti-apoptotic path-
way. For example, in breast cancer cells, MCF-7, PrP inhibits pro-apoptotic Bax
conformational change occurring initially in Bax activation to prevent cell death
[ 22 ]. In addition, cancer cells expressing PrP have accelerated cell cycle. PrP has
been shown transcriptionally activating cyclin D1 expression to promote G1/S tran-
sition of human gastric cancer cells SGC 7901 and AGS [ 23 ]. Since PrP can be
detected in the nuclei of some cancer cells, it remains to be determined if PrP can
directly bind to the promoter region of cyclin D1, thus activating its expression.
More importantly, PrP expression level is positively correlated with multidrug
13 Prion Protein Exacerbates Tumorigenesis