Reconstitution of TGFBR2-Mediated Signaling Causes Upregulation of GDF-15 in HCT116 Colorectal Cancer Cells

Jennifer Lee; Fabia Fricke; Uwe Warnken; Martina Schnölzer; Jürgen Kopitz; Johannes Gebert

doi:10.1371/journal.pone.0131506

Reconstitution of TGFBR2-Mediated Signaling Causes Upregulation of GDF-15 in HCT116 Colorectal Cancer Cells

PLoS One. 2015 Jun 26;10(6):e0131506. doi: 10.1371/journal.pone.0131506. eCollection 2015.

Authors

Jennifer Lee¹, Fabia Fricke¹, Uwe Warnken², Martina Schnölzer², Jürgen Kopitz¹, Johannes Gebert¹

Affiliations

¹ Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cancer Early Detection, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

Although inactivating frameshift mutations in the Transforming growth factor beta receptor type 2 (TGFBR2) gene are considered as drivers of microsatellite unstable (MSI) colorectal tumorigenesis, consequential alterations of the downstream target proteome are not resolved completely. Applying a click-it chemistry protein labeling approach combined with mass spectrometry in a MSI colorectal cancer model cell line, we identified 21 de novo synthesized proteins differentially expressed upon reconstituted TGFBR2 expression. One candidate gene, the TGF-ß family member Growth differentiation factor-15 (GDF-15), exhibited TGFBR2-dependent transcriptional upregulation causing increased intracellular and extracellular protein levels. As a new TGFBR2 target gene it may provide a link between the TGF-ß branch and the BMP/GDF branch of SMAD-mediated signaling.

Publication types

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

MeSH terms

Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Gene Expression Regulation, Neoplastic / drug effects
Growth Differentiation Factor 15 / genetics*
Growth Differentiation Factor 15 / metabolism
Growth Differentiation Factor 15 / pharmacology
HCT116 Cells
Humans
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / physiology*
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta / genetics
Receptors, Transforming Growth Factor beta / physiology*
Signal Transduction / drug effects
Signal Transduction / genetics
Smad Proteins / metabolism
Transcriptional Activation / genetics
Up-Regulation / drug effects
Up-Regulation / genetics

Substances

GDF15 protein, human
Growth Differentiation Factor 15
Receptors, Transforming Growth Factor beta
Smad Proteins
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type II

Grants and funding

Financial support was provided by Deutsche Forschungsgemeinschaft (GE592/6-2) to JK and JG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.