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KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells.
Gastroenterology. 2004 Aug; 127(2):607-20.G

Abstract

BACKGROUND & AIMS

Smad-regulated transcription plays a central role in transforming growth factor (TGF)-beta-induced cell growth inhibition and tumor suppression. Like the Smads, KLF11 is an early response transcription factor that mediates TGF-beta-induced growth inhibition in untransformed epithelial cells. Here, we investigated the functional implications of KLF11 in TGF-beta signaling and transcription in normal epithelial as well as pancreatic cancer cells.

METHODS

The effects of KLF11 on TGF-beta signaling and transcription were examined on the levels of reporter transactivation, Smad2 phosphorylation, and expression of endogenous TGF-beta-regulated genes. Promoter analysis, real-time polymerase chain reaction, and coimmunoprecipitation studies were performed to study KLF11-induced and mSin3A corepressor-mediated repression of Smad7. Erk-induced KLF11 phosphorylation was examined in vitro and in vivo, and its impact on KLF11-mSin3A-mediated Smad7 repression was verified in pancreatic cancer cells using site-directed mutagenesis.

RESULTS

KLF11 potentiates TGF-beta signaling by terminating the inhibitory Smad7 loop. Mechanistically, KLF11 represses TGF-beta-induced transcription from the Smad7 promoter by recruiting mSin3a via GC-rich sites. This function is inhibited in pancreatic cancer cells with oncogenic Ras mutations, in which Erk/mitogen-activated protein kinase phosphorylates KLF11, leading to disruption of KLF11-mSin3a interaction. Expression of an Erk-insensitive KLF11 mutant restores both mSin3a binding and Smad7 repression and results in enhanced TGF-beta signaling in pancreatic cancer cells.

CONCLUSIONS

These results define a novel mechanism in TGF-beta-regulated gene expression. KLF11 potentiates Smad-signaling activity in normal epithelial cells through termination of the negative feedback loop imposed by Smad7. The fact that this function of KLF11 is inhibited by oncogenic Erk/mitogen-activated protein kinase in pancreatic cancer cells emphasizes the importance of this mechanism for oncogenesis.

Authors+Show Affiliations

Department of Internal Medicine, University of Ulm, Germany. volker.ellenrieder@medizin.uni-ulm.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15300592

Citation

Ellenrieder, Volker, et al. "KLF11 Mediates a Critical Mechanism in TGF-beta Signaling That Is Inactivated By Erk-MAPK in Pancreatic Cancer Cells." Gastroenterology, vol. 127, no. 2, 2004, pp. 607-20.
Ellenrieder V, Buck A, Harth A, et al. KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. Gastroenterology. 2004;127(2):607-20.
Ellenrieder, V., Buck, A., Harth, A., Jungert, K., Buchholz, M., Adler, G., Urrutia, R., & Gress, T. M. (2004). KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. Gastroenterology, 127(2), 607-20.
Ellenrieder V, et al. KLF11 Mediates a Critical Mechanism in TGF-beta Signaling That Is Inactivated By Erk-MAPK in Pancreatic Cancer Cells. Gastroenterology. 2004;127(2):607-20. PubMed PMID: 15300592.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. AU - Ellenrieder,Volker, AU - Buck,Anita, AU - Harth,Ana, AU - Jungert,Kerstin, AU - Buchholz,Malte, AU - Adler,Guido, AU - Urrutia,Raul, AU - Gress,Thomas M, PY - 2004/8/10/pubmed PY - 2004/9/15/medline PY - 2004/8/10/entrez SP - 607 EP - 20 JF - Gastroenterology JO - Gastroenterology VL - 127 IS - 2 N2 - BACKGROUND & AIMS: Smad-regulated transcription plays a central role in transforming growth factor (TGF)-beta-induced cell growth inhibition and tumor suppression. Like the Smads, KLF11 is an early response transcription factor that mediates TGF-beta-induced growth inhibition in untransformed epithelial cells. Here, we investigated the functional implications of KLF11 in TGF-beta signaling and transcription in normal epithelial as well as pancreatic cancer cells. METHODS: The effects of KLF11 on TGF-beta signaling and transcription were examined on the levels of reporter transactivation, Smad2 phosphorylation, and expression of endogenous TGF-beta-regulated genes. Promoter analysis, real-time polymerase chain reaction, and coimmunoprecipitation studies were performed to study KLF11-induced and mSin3A corepressor-mediated repression of Smad7. Erk-induced KLF11 phosphorylation was examined in vitro and in vivo, and its impact on KLF11-mSin3A-mediated Smad7 repression was verified in pancreatic cancer cells using site-directed mutagenesis. RESULTS: KLF11 potentiates TGF-beta signaling by terminating the inhibitory Smad7 loop. Mechanistically, KLF11 represses TGF-beta-induced transcription from the Smad7 promoter by recruiting mSin3a via GC-rich sites. This function is inhibited in pancreatic cancer cells with oncogenic Ras mutations, in which Erk/mitogen-activated protein kinase phosphorylates KLF11, leading to disruption of KLF11-mSin3a interaction. Expression of an Erk-insensitive KLF11 mutant restores both mSin3a binding and Smad7 repression and results in enhanced TGF-beta signaling in pancreatic cancer cells. CONCLUSIONS: These results define a novel mechanism in TGF-beta-regulated gene expression. KLF11 potentiates Smad-signaling activity in normal epithelial cells through termination of the negative feedback loop imposed by Smad7. The fact that this function of KLF11 is inhibited by oncogenic Erk/mitogen-activated protein kinase in pancreatic cancer cells emphasizes the importance of this mechanism for oncogenesis. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/15300592/KLF11_mediates_a_critical_mechanism_in_TGF_beta_signaling_that_is_inactivated_by_Erk_MAPK_in_pancreatic_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016508504008649 DB - PRIME DP - Unbound Medicine ER -