Abstract
Our previous data demonstrated that Ras activation was necessary and sufficient for transforming growth factor-β (TGFβ)-mediated Erk1 activation, and was required for TGFβ up-regulation of the Cdk inhibitors (CKI's) p27Kip1 and p21Cip1 (KM Mulder and SL Morris, J. Biol. Chem., 267, 5029 – 5031, 1992; MT Hartsough and KM Mulder, J. Biol. Chem., 270, 7117 – 7124, 1995; MT Hartsough et al., J. Biol. Chem., 271, 22368 – 22375, 1996 and J Yue et al., Oncogene, 17, 47 – 55, 1998). Here we examined the role of Ras in TGFβ-mediated effects on a rat homolog of Smad1 (termed RSmad1). We demonstrate that both TGFβ and bone morphogenetic protein (BMP) can induce endogenous Smad1 phosphorylation in intestinal epithelial cells (IECs). The combination of transient expression of RSmad1 and TGFβ treatment had an additive effect on induction of the TGFβ-responsive reporter 3TP-lux. Either inactivation of Ras by stable, inducible expression of a dominant-negative mutant of Ras (RasN17) or addition of MAP and ERK kinase (MEK) inhibitor PD98059 to cells significantly decreased the ability of both TGFβ and BMP to induce phosphorylation of endogenous Smad1 in IECs. Moreover, either inactivation of Ras or addition of PD98059 to IEC 4-1 cells inhibited the ability of RSmad1 to regulate 3TP luciferase activity in both the presence and absence of TGFβ. Collectively, our data indicate that TGFβ can regulate RSmad1 function in epithelial cells, and that the Ras/MEK pathway is partially required for TGFβ-mediated regulation of RSmad1.
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Abbreviations
- TGFβ:
-
transforming growth factor-beta
- BMP:
-
bone morphogenetic protein
- RasN17:
-
dominant-negative Ras mutant
- IECs:
-
intestinal epithelial cells
- MBP:
-
myelin-basic protein
- MAPK:
-
mitogen-activated protein kinase
- Smads:
-
Sma and Mad homologs
- RSmad1:
-
rat Smad1
- MEK:
-
MAP and ERK kinase
- SDS – PAGE:
-
SDS polyacrylamide gel electrophoresis
- CKIs:
-
cyclin-dependent kinsase inhibitors
- Erk:
-
extracellular signal-regulated kinase
- SAPK/JNK:
-
stress-activated protein kinase/c-Jun N-terminal kinase
- SM:
-
Supplemental McCoys 5A medium
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Acknowledgements
We wish to thank M Morin (Pfizer Pharmaceuticals, Groton, CT, USA) for generously supplying the TGFβ3, J Massagué (Memorial Sloan-Kettering Cancer Center, New York, NY, USA) for the anti-Smad1 antibody and p3TP-Lux and V Rosen (Genetics Institute, Cambridge, MA, USA) for BMP2. We also thank Andrew Stevenson for assisting with the preparation of the manuscript. This work was supported by National Institutes of Health Grants CA51425, CA54816, and CA68444 to KMM. KMM is a recipient of National Institutes of Health Research Career Development Award K04 CA59552.
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Yue, J., Frey, R. & Mulder, K. Cross-talk between the Smad1 and Ras/MEK signaling pathways for TGFβ. Oncogene 18, 2033–2037 (1999). https://doi.org/10.1038/sj.onc.1202521
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DOI: https://doi.org/10.1038/sj.onc.1202521
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