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the biogenesis of pro-PrP. In addition, in cancer cells without FLNa expression,
pro-PrP can modify cytoskeleton structure by affecting cofilin/F-actin axis, thus
influencing cancer cell movement. Besides pro-PrP, we showed that GPI-anchored
unglycosylated PrP can elevate cell mobility by interacting with VEGFR2, thus
stimulating cell migration under serum-free condition. Besides affecting cancer cell
motility, overexpressed PrP or doppel (Dpl) in cancer cells has been shown to
increase cell proliferation, multiple drug resistance, and angiogenesis, thus, proteins
from PrP gene family by affecting important processes via multiple pathways for
cancer cell growth exacerbating tumorigenesis.
Keywords Prion protein • Doppel protein • Tumorigenesis • Signal transduction •
Cell motility
13.1 Introduction
The prion gene family is comprised of four genes, PRNP, PRND, SPRN, and PRNT,
among which PRNP, PRND, and PRNT genes are located within a 55 kb region on
20p13 locus (PRNP-20 kb-PRND-3 kb-PRNT) in human. PRNP, PRND, and SPRN
encode prion protein (PrP), doppel (Dpl) which is homologous to the C-terminus of
PRP and shadoo (Sho) which is homologous to the N-terminus of PrP, respectively,
whereas PRNT is probably a pseudogene due to multiple large transposon insertions
[ 1 ]. Positive immunoreaction against antibody specific to Prt, the potential protein
product of PRNT, was reported in the testis and ejaculated spermatozoa of ovine [ 2 ].
However, it remains to be seen that Prt is indeed expressing in those tissues. PRNP
and SPRN are present in all vertebrates, whereas PRND is detected in tetrapods but
not in avians probably due to its lost in an early ancestor of birds [ 1 , 3 , 4 ]. The pres-
ence of PRNT in mammals is controversial; some reported that PRNT is only identi-
fied in primates, whereas others argued that it is highly conserved in mammals [ 1 ,
3 , 4 ]. The evolutionary origin of PRNP remains ambiguous although multiple lines
of evidence implicated that PrP may evolve from ZIP family of metal ion transport-
ers [ 5 ]. It is likely that during the emergence of metazoan, a prion-like ectodomain
in a subbranch of ZIP genes composing of ZIP5, ZIP6, and ZIP10 was generated by
a cysteine-flanked core domain inserting in a preexisting ZIP ancestor gene, which
then presumably evolved as the founder gene for prion [ 6 ]. The amino acid sequence
of PrP can be divided into two domains, the N-terminus flexible domain and the
C-terminus globular domain. PrP is expressed in many cells, such as neuron cells in
central nervous system (CNS), epithelial cells in the gut and intestine, smooth mus-
cle cells of blood vessel, islet cells of the pancreas, monocytes and lymphocytes,
etc. It’s generally undetectable in hepatocytes, ductal epithelial cells in the pancreas,
and the kidney. The regulation of tissue-specific PrP expression is not clear. It has
been shown that the 1.2 kb sequence upstream of PRNP contains promoter and
repressor elements with major promoter activity adjacent to the 5′ region of exons 1
and 2 whereas suppressor activity adjacent to the 5′ region of intron 1 [ 7 ].
X. Yang et al.