Abstract
LIM-only protein 4 (LMO4) plays critical roles in mammalian development, and has been proposed to play roles in epithelial oncogenesis, including breast cancer. As LMO4 is highly expressed in the epithelial compartments at locations of active mesenchymal-epithelial interactions, we reasoned that LMO4 might act by modulating signaling pathways involved in mesenchymal-epithelial signaling. One such candidate signal is the transforming growth factor-β (TGFβ) cytokine pathway, which plays important roles both in development and cancer. We show here that the transcriptional response to TGFβ in epithelial cells is sensitive to LMO4 levels; both up- and downregulation of LMO4 can enhance TGFβ signaling as assessed by a TGFβ-responsive reporter gene. Furthermore, LMO4 can interact with the MH1 and linker domains of receptor-mediated Smad proteins, and associate with the endogenous TGFβ-responsive Plasminogen Activator Inhibitor-1 gene promoter in a TGFβ-dependent manner, suggesting that such interactions may mediate the effects of LMO4 on TGFβ signaling. When introduced into mammary epithelial cells, LMO4 potentiated the growth-inhibitory effects of TGFβ in those cells. These results define a new function for LMO4 as a coactivator in TGFβ signaling, and provide a potential novel mechanism for LMO4-mediated regulation in development and oncogenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2920-2930 |
| Number of pages | 11 |
| Journal | Oncogene |
| Volume | 25 |
| Issue number | 20 |
| DOIs | |
| State | Published - May 11 2006 |
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Keywords
- Cellular proliferation
- LMO4
- Mammary gland epithelial cells
- Smads
- Transforming growth factorβ
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells. / Lu, Z.; Lam, Kit; Wang, N.; Xu, X.; Cortes, M.; Andersen, B.
In: Oncogene, Vol. 25, No. 20, 11.05.2006, p. 2920-2930.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells
AU - Lu, Z.
AU - Lam, Kit
AU - Wang, N.
AU - Xu, X.
AU - Cortes, M.
AU - Andersen, B.
PY - 2006/5/11
Y1 - 2006/5/11
N2 - LIM-only protein 4 (LMO4) plays critical roles in mammalian development, and has been proposed to play roles in epithelial oncogenesis, including breast cancer. As LMO4 is highly expressed in the epithelial compartments at locations of active mesenchymal-epithelial interactions, we reasoned that LMO4 might act by modulating signaling pathways involved in mesenchymal-epithelial signaling. One such candidate signal is the transforming growth factor-β (TGFβ) cytokine pathway, which plays important roles both in development and cancer. We show here that the transcriptional response to TGFβ in epithelial cells is sensitive to LMO4 levels; both up- and downregulation of LMO4 can enhance TGFβ signaling as assessed by a TGFβ-responsive reporter gene. Furthermore, LMO4 can interact with the MH1 and linker domains of receptor-mediated Smad proteins, and associate with the endogenous TGFβ-responsive Plasminogen Activator Inhibitor-1 gene promoter in a TGFβ-dependent manner, suggesting that such interactions may mediate the effects of LMO4 on TGFβ signaling. When introduced into mammary epithelial cells, LMO4 potentiated the growth-inhibitory effects of TGFβ in those cells. These results define a new function for LMO4 as a coactivator in TGFβ signaling, and provide a potential novel mechanism for LMO4-mediated regulation in development and oncogenesis.
AB - LIM-only protein 4 (LMO4) plays critical roles in mammalian development, and has been proposed to play roles in epithelial oncogenesis, including breast cancer. As LMO4 is highly expressed in the epithelial compartments at locations of active mesenchymal-epithelial interactions, we reasoned that LMO4 might act by modulating signaling pathways involved in mesenchymal-epithelial signaling. One such candidate signal is the transforming growth factor-β (TGFβ) cytokine pathway, which plays important roles both in development and cancer. We show here that the transcriptional response to TGFβ in epithelial cells is sensitive to LMO4 levels; both up- and downregulation of LMO4 can enhance TGFβ signaling as assessed by a TGFβ-responsive reporter gene. Furthermore, LMO4 can interact with the MH1 and linker domains of receptor-mediated Smad proteins, and associate with the endogenous TGFβ-responsive Plasminogen Activator Inhibitor-1 gene promoter in a TGFβ-dependent manner, suggesting that such interactions may mediate the effects of LMO4 on TGFβ signaling. When introduced into mammary epithelial cells, LMO4 potentiated the growth-inhibitory effects of TGFβ in those cells. These results define a new function for LMO4 as a coactivator in TGFβ signaling, and provide a potential novel mechanism for LMO4-mediated regulation in development and oncogenesis.
KW - Cellular proliferation
KW - LMO4
KW - Mammary gland epithelial cells
KW - Smads
KW - Transforming growth factorβ
UR - http://www.scopus.com/inward/record.url?scp=33646705880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646705880&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1209318
DO - 10.1038/sj.onc.1209318
M3 - Article
VL - 25
SP - 2920
EP - 2930
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 20
ER -