Biomedical Engineering Reference
In-Depth Information
The Notch pathway is linked to both oncogenic effects and tumor suppressor
functions (Weng and Aster 2004). Jagged-1 is overexpressed in metastatic
prostate cancer (Santagata et al. 2004), and knockdown experiments revealed
that its loss inhibits prostate cancer cell growth and forces S phase cell cycle
arrest (Zhang et al. 2006). In addition, the levels of Notch1 expression are
greater in murine prostate tumor cells, but constitutive expression of the active
form of Notch1 inhibits DU145, LNCaP, and PC3 cell line proliferation (Shou
et al. 2001). Thus, the effects of Notch signaling may depend on the timing and
level of activation within the cell.
Studies have shown that Notch signal transduction is important to normal
prostate epithelial cell proliferation and differentiation (Wang et al. 2004, 2006;
Shou et al. 2001). Notch1 is expressed in basal epithelial prostate cells (Shou
et al. 2001), and transgenic mouse models in which Notch-expressing cells can
be specifically ablated reveal that prostate branching morphogenesis, growth,
and differentiation of early post-natal prostate cells in culture are all inhibited.
Furthermore, prostate re-growth in castrated mice requires Notch1 expression
(Wang et al. 2004). A recent study used g-secretase inhibitors to block Notch
maturation of neonatal prostate cells in culture and evaluated Notch1 condi-
tional knockout mice (Wang et al. 2006). Their data indicate that loss of Notch
signaling increased epithelial progenitor cell proliferation and impaired differ-
entiation, suggesting that prostate progenitor cell proliferation is negatively
regulated by Notch. These progenitor cells also express K8 and K14, markers of
normal prostate stem and TA cells (Rizzo et al. 2005). Thus, proper control of
the Notch pathway appears to be important to regulate a balance between SC
maintenance and activation of differentiation within the prostate. It is likely
that Notch serves the same function in prostate CSCs, as microarray data from
CD44 + CD24 LNCaP tumor-initiating cells confirm a reduced expression of
Notch 1-3 and Jagged 1 relative to the non-stem cell population (EMH unpub-
lished observations). Interestingly, Notch1 was preferentially expressed in pros-
tate cancer side population cells (Patrawala et al. 2005).
4.4 Nanog, Oct3/4, and Sox2 Transcriptional Network
The transcription factors Nanog, Oct3/4, and Sox2 are important for self-
renewal and inhibition of differentiation in embryonic stem (ES) cells (Pan
and Thomson 2007). The expression of Oct3/4 and Nanog can be sustained
by, among other mechanisms, the Wnt pathway (Sato et al. 2004). Further-
more, the transcription factors Tcf3, which is downstream in the Wnt pathway,
and p53 limit Nanog expression to allow the cell to initiate differentiation, and
loss of Tcf3 enhances the level of Nanog in ES cells (Pereira et al. 2006). Nanog,
a homeobox transcription factor, blocks ES cell differentiation and thus reg-
ulates self-renewal. The POU-domain protein Oct3/4 (octamer-binding tran-
scription factor 3/4) can either activate or repress transcription depending on
Search WWH ::




Custom Search