Page 175 - Vitamin D and Cancer

162 E. Gocek and G.P. Studzinski

7.3.2.3 C/EBP B Transcription Factor as an Effector of Monocytic
Differentiation

One of the downstream targets of the MAPK-RSK pathway is a nuclear transcription
factor, the CAAT and Enhancer Binding Protein b (C/EBP b). This transcription factor
has been reported to be activated by phosphorylation both by ERK [192] and by RSK
[193], and can interact directly with the promoter of CD14, one of the principal markers
of monocytic differentiation [194], as illustrated in Fig. 7.4. We showed that the expres-
sion of C/EBP b is increased by 1,25D in parallel with markers of differentiation;
conversely, the knockdown of its expression by antisense oligonucleotides, or of its
transcriptional activity by “decoy” promoter competition, inhibited 1,25D-induced
differentiation [195]. In an additional study, the data suggested that 1,25D induced
phosphorylation of C/EBP b isoforms on Thr235, and that the C/EBP b-2 isoform is
one of the principal differentiation-related transcription factors in this system [87].
These findings suggest that 1,25D can induce leukemic progenitor cells, which
have the potential to differentiate into several hematopoietic lineages, to become
nonproliferating monocyte-like cells by changing the ratio of nuclear transcription
factors in a manner that permits this form of differentiation [196]. In this scenario,
the event that initiates leukemic transformation, such as a mutation, alters the
proper balance of transcription factor activity necessary for normal granulocytic
cell differentiation. However, 1,25D-induced expression of C/EBP b then allows
the cells to bypass this block to granulocytic differentiation by becoming mono-
cyte-like cells instead (Fig. 7.5).
C/EBP α, β,ε (+) EP C/EBP β (+) C/EBP α (–) EP C/EBP α(–)

P P P P

P P P P

1,25D C/EBP β ↑

Granulocytes Monocytes Granulocytes Monocytes
Fig. 7.5 The suggested role of CAAT/enhancer binding protein b in 1,25D-induced bypass of the
differentiation block in leukemia cells. In this scenario, C/EBP a is indispensable for normal
granulopoiesis, while C/EBP b regulates monocytic differentiation. When C/EBP a is mutated or
inactivated and granulopoiesis is blocked, immature myeloid cells accumulate in the bone marrow
and appear in the peripheral blood resulting in acute myeloid leukemia (AML). 1,25D-induced
expression of C/EBP b may allow the cells to bypass this block to granulocytic differentiation by
switching the lineage of cell differentiation from granulocytes to monocytes