Interestingly, OVOL2 expression is activated by GRHL2 in
kidney epithelial cells, and ectopic OVOL2 expression is sufficient
to rescue the expression of CDH1, RAB25, and CLDN4 after
GRHL2 knockdown, restoring luminal expansion in renal epithelial
cysts in vitro [62]. Thus, in contrast to the described role of
OVOL2 as a transcriptional repressor [76], this study suggests
that OVOL2 may co-operate with GRHL2 to induce activation
of epithelial functional genes through as-yet unidentified
mechanisms.
5.3 EpitheliumSpecific Ets-Domain
Containing TFs
Recent attention on epithelium-specific Ets (ESE) TFs, a subfamily
of E26 transformation specific (Ets)-domain containing TFs, has
revealed potential roles as negative regulators of EMT and enforcers
of the epithelial state. Mice with targeted mutations of ESE subfamily member ELF5/ESE2 specifically in the mammary gland
display impaired lobulogenesis, decreased AJs, and increased mesenchymal markers, and ELF5 represses the Slug promoter in mouse
mammary cells [77]. Another ESE subfamily member, ELF3/
ESE1/ESX, is a negative regulator of EMT in ovarian cancer
cells, and ELF3 overexpression induces MET with downregulation
of Slug [78]. Moreover, ELF3 nuclear localization correlates with
epithelial gene expression in ovarian tumors and with improved
survival in patients with ovarian cancer [78]. ELF3 inhibits EMT
in bladder carcinoma cells concomitant with decreased CDH2 and
Slug [79]. Notably, ELF3 null mice display disrupted morphogenesis of small intestinal epithelium with impaired differentiation of
absorptive enterocyte and goblet cell lineages [80], and loss of ELF
causes delayed epithelial repair after selective injury to airway epithelium in adult mice [81]. Another ESE family member EHF
directly represses TWIST1 and ZEB2 to control epithelial characteristics of prostate epithelial cells, and loss of EHF induces EMT
[82]. ELF3, ELF5, and EHF are expressed specifically in various
epithelial tissues in adult humans and mice [83], supporting broad
roles in establishing and maintaining epithelial characteristics
(reviewed in [84]).
5.4 Singleminded 2
The bHLH TF singleminded 2 (Sim2) restricts EMT during mammary gland morphogenesis, and Sim2 null mice display invasive
TEB cells in developing mammary gland tips. Furthermore, silencing Sim2 induces EMT in a mammary epithelial cell line, and Sim2
directly represses the SNAIL2 promoter [85]. Together, the above
studies suggest that ELF5, OVOL2, and Sim2 may co-operate to
promote MET during mammary gland morphogenesis.
5.5 SRY-Box 3
A study of chick gastrulation revealed a fundamental role for
SRY-box 3 (Sox3) in defining mesenchymal tissue boundaries.
Here, Sox3 represses the Slug promoter to define non-ingressing
ectoderm, whereas Slug represses the Sox3 promoter in ingressing
52
John-Poul Ng-Blichfeldt and Katja Ro ¨ per
kidney epithelial cells, and ectopic OVOL2 expression is sufficient
to rescue the expression of CDH1, RAB25, and CLDN4 after
GRHL2 knockdown, restoring luminal expansion in renal epithelial
cysts in vitro [62]. Thus, in contrast to the described role of
OVOL2 as a transcriptional repressor [76], this study suggests
that OVOL2 may co-operate with GRHL2 to induce activation
of epithelial functional genes through as-yet unidentified
mechanisms.
5.3 EpitheliumSpecific Ets-Domain
Containing TFs
Recent attention on epithelium-specific Ets (ESE) TFs, a subfamily
of E26 transformation specific (Ets)-domain containing TFs, has
revealed potential roles as negative regulators of EMT and enforcers
of the epithelial state. Mice with targeted mutations of ESE subfamily member ELF5/ESE2 specifically in the mammary gland
display impaired lobulogenesis, decreased AJs, and increased mesenchymal markers, and ELF5 represses the Slug promoter in mouse
mammary cells [77]. Another ESE subfamily member, ELF3/
ESE1/ESX, is a negative regulator of EMT in ovarian cancer
cells, and ELF3 overexpression induces MET with downregulation
of Slug [78]. Moreover, ELF3 nuclear localization correlates with
epithelial gene expression in ovarian tumors and with improved
survival in patients with ovarian cancer [78]. ELF3 inhibits EMT
in bladder carcinoma cells concomitant with decreased CDH2 and
Slug [79]. Notably, ELF3 null mice display disrupted morphogenesis of small intestinal epithelium with impaired differentiation of
absorptive enterocyte and goblet cell lineages [80], and loss of ELF
causes delayed epithelial repair after selective injury to airway epithelium in adult mice [81]. Another ESE family member EHF
directly represses TWIST1 and ZEB2 to control epithelial characteristics of prostate epithelial cells, and loss of EHF induces EMT
[82]. ELF3, ELF5, and EHF are expressed specifically in various
epithelial tissues in adult humans and mice [83], supporting broad
roles in establishing and maintaining epithelial characteristics
(reviewed in [84]).
5.4 Singleminded 2
The bHLH TF singleminded 2 (Sim2) restricts EMT during mammary gland morphogenesis, and Sim2 null mice display invasive
TEB cells in developing mammary gland tips. Furthermore, silencing Sim2 induces EMT in a mammary epithelial cell line, and Sim2
directly represses the SNAIL2 promoter [85]. Together, the above
studies suggest that ELF5, OVOL2, and Sim2 may co-operate to
promote MET during mammary gland morphogenesis.
5.5 SRY-Box 3
A study of chick gastrulation revealed a fundamental role for
SRY-box 3 (Sox3) in defining mesenchymal tissue boundaries.
Here, Sox3 represses the Slug promoter to define non-ingressing
ectoderm, whereas Slug represses the Sox3 promoter in ingressing
52
John-Poul Ng-Blichfeldt and Katja Ro ¨ per