Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway.
KEPI is a protein kinase C-potentiated inhibitory protein for type 1 Ser/Thr protein phosphatases. We found no or reduced expression of KEPI in breast cancer cell lines, breast tumors and metastases in comparison to normal breast cell lines and tissues, respectively. KEPI protein expression and ubiquitous localization was detected with a newly generated antibody. Ectopic KEPI expression in MCF7 breast cancer cells induced differential expression of 95 genes, including the up-regulation of the tumor suppressors EGR1 (early growth response 1) and PTEN (phosphatase and tensin homolog), which is regulated by EGR1. We further show that the up-regulation of EGR1 in MCF7/KEPI cells is mediated by MEK-ERK signaling. The inhibition of this pathway by the MEK inhibitor UO126 led to a strong decrease in EGR1 expression in MCF7/KEPI cells. These results reveal a novel role for KEPI in the regulation of the tumor suppressor gene EGR1 via activation of the MEK-ERK MAPK pathway.
Wenzel
Katrin
K
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin, Germany. kwenzel@mdc-berlin.de
Daskalow
Katjana
K
Herse
Florian
F
Seitz
Susanne
S
Zacharias
Ute
U
Schenk
Jörg A
JA
Schulz
Herbert
H
Hubner
Norbert
N
Micheel
Burkhard
B
Schlag
Peter M
PM
Osterziel
Karl J
KJ
Ozcelik
Cemil
C
Scherneck
Siegfried
S
Jandrig
Burkhard
B
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D047908:Intracellular Signaling Peptides and Proteins; C454464:PPP1R14C protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human