Conserved regulation of MAP kinase expression by PUF RNA-binding proteins.
Mitogen-activated protein kinase (MAPK) and PUF (for Pumilio and FBF [fem-3 binding factor]) RNA-binding proteins control many cellular processes critical for animal development and tissue homeostasis. In the present work, we report that PUF proteins act directly on MAPK/ERK-encoding mRNAs to downregulate their expression in both the Caenorhabditis elegans germline and human embryonic stem cells. In C. elegans, FBF/PUF binds regulatory elements in the mpk-1 3' untranslated region (3' UTR) and coprecipitates with mpk-1 mRNA; moreover, mpk-1 expression increases dramatically in FBF mutants. In human embryonic stem cells, PUM2/PUF binds 3'UTR elements in both Erk2 and p38alpha mRNAs, and PUM2 represses reporter constructs carrying either Erk2 or p38alpha 3' UTRs. Therefore, the PUF control of MAPK expression is conserved. Its biological function was explored in nematodes, where FBF promotes the self-renewal of germline stem cells, and MPK-1 promotes oocyte maturation and germ cell apoptosis. We found that FBF acts redundantly with LIP-1, the C. elegans homolog of MAPK phosphatase (MKP), to restrict MAPK activity and prevent apoptosis. In mammals, activated MAPK can promote apoptosis of cancer cells and restrict stem cell self-renewal, and MKP is upregulated in cancer cells. We propose that the dual negative regulation of MAPK by both PUF repression and MKP inhibition may be a conserved mechanism that influences both stem cell maintenance and tumor progression.
Lee
Myon-Hee
MH
Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Hook
Brad
B
Pan
Guangjin
G
Kershner
Aaron M
AM
Merritt
Christopher
C
Seydoux
Geraldine
G
Thomson
James A
JA
Wickens
Marvin
M
Kimble
Judith
J
D000818:Animals; D015153:Blotting, Western; D017173:Caenorhabditis elegans; D015971:Gene Expression Regulation, Enzymologic; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D020928:Mitogen-Activated Protein Kinases