Page 170 - Vitamin D and Cancer

7 Induction of Differentiation in Cancer Cells by Vitamin D 157

Growth factors/Cytokines Cytokines/Stress/UV
1,25D

Ras
High KSR-1 ?
Raf-1 MEKKs,etc

MEK 1/2 MKK4/7 MKK3/6
VDR
– ?
p35/Cdk5 JNK1/2 p38
?
p90RSK
EGR1
VDR AP-1 ?
p35 P-Thr235
pRb
VDR RXR ? C/EBPβ C/EBPβ CD14
C/EBPβ
VDRE

Fig. 7.4 Later stages of 1,25D-induced differentiation. This figure illustrates that the transcrip-
tion factor Egr-1, known to be upregulated by 1,25D (189), can increase the expression of p35/
Nck5a (p35) activator of Cdk5. Cdk5 activated by p35 then can phosphorylate MEK on Thr286,
a site which inactivates it [200], as shown by the Q symbol. This diminishes ERK1/2 activity,
downstream from MEK (not shown here), but Raf-1 can activate p90RSK directly, which in turn
activates the transcription factor C/EBP b, perhaps bound to pRb, and increases the expression of
CD14, as part of monocytic differentiation. The activation of p90RSK may also be increased by
the Jun N-terminal kinase (JNK) pathway, which also activates AP-1, and may lead to VDR
expression. The interplay between the signaling by 1,25D, growth factor, and stress add to the
overall complexity of the induction of the monocytic phenotype

also operative, but remain to be convincingly demonstrated. The details of the scheme
are described below.

7.3.1 Signaling of Monocytic Differentiation by MAPK
and Parallel Pathways

Early in our investigations we recognized that 1,25D-induced monocytic differen-
tiation is not a single continuous process, but a series of events that can be divided
into at least two overlapping phases. In the first phase, which lasts 24–48 h, the cells
continue in the normal cell cycle while expressing markers of monocytic pheno-
type, such as CD14 and NSE. In the next phase, the G1 to S phase cell cycle block
becomes apparent, and the expression of CD11b is also prominent, indicating a