An induced Ets repressor complex regulates growth arrest during terminal macrophage differentiation.
Defining the molecular mechanisms that coordinately regulate proliferation and differentiation is a central issue in development. Here, we describe a mechanism in which induction of the Ets repressor METS/PE1 links terminal differentiation to cell cycle arrest. Using macrophages as a model, we provide evidence that METS/PE1 blocks Ras-dependent proliferation without inhibiting Ras-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Antiproliferative effects of METS require its interaction with DP103, a DEAD box-containing protein that assembles a novel corepressor complex. Functional interactions between the METS/DP103 complex and E2F/ pRB family proteins are also necessary for inhibition of cellular proliferation, suggesting a combinatorial code that directs permanent cell cycle exit during terminal differentiation.
Klappacher
Günter W
GW
Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Lunyak
Victoria V
VV
Sykes
David B
DB
Sawka-Verhelle
Dominique
D
Sage
Julien
J
Brard
Gyan
G
Ngo
Sally D
SD
Gangadharan
Denise
D
Jacks
Tyler
T
Kamps
Mark P
MP
Rose
David W
DW
Rosenfeld
Michael G
MG
Glass
Christopher K
CK
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D055541:DEAD Box Protein 20; D053487:DEAD-box RNA Helicases; D005656:Fungal Proteins; D018816:Genes, cdc / Q000502:physiology; D006168:Guinea Pigs; D007107:Immune System / Q000254:growth & development* / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins; D020365:RNA Helicases / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors; D018631:ras Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; C412319:ETV3 protein, mouse; D005656:Fungal Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C489485:Rbl1 protein, mouse; C493839:Rbl2 protein, rat; D012097:Repressor Proteins; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors; D012697:Serine Endopeptidases; D055541:DEAD Box Protein 20; C485624:Ddx20 protein, mouse; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases; D018631:ras Proteins