p57(Kip2) cooperates with Nurr1 in developing dopamine cells.
Cyclin-dependent kinase inhibitors of the Cip/Kip family play critical roles in regulating cell proliferation during embryogenesis. However, these proteins also influence cell differentiation by mechanisms that have remained unknown. Here we show that p57Kip2 is expressed in postmitotic differentiating midbrain dopamine cells. Induction of p57Kip2 expression depends on Nurr1, an orphan nuclear receptor that is essential for dopamine neuron development. Moreover, analyses of p57Kip2 gene-targeted mice revealed that p57Kip2 is required for the maturation of midbrain dopamine neuronal cells. Additional experiments in a dopaminergic cell line demonstrated that p57Kip2 can promote maturation by a mechanism that does not require p57Kip2-mediated inhibition of cyclin-dependent kinases. Instead, evidence indicates that p57Kip2 functions by a direct protein-protein interaction with Nurr1. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57Kip2 influences postmitotic differentiation of dopamine neurons.
Joseph
Bertrand
B
The Ludwig Institute for Cancer Research, Box 240, S-171 77 Stockholm, Sweden.
Wallén-Mackenzie
Asa
A
Benoit
Gérard
G
Murata
Takashi
T
Joodmardi
Eliza
E
Okret
Sam
S
Perlmann
Thomas
T
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D050761:Cyclin-Dependent Kinase Inhibitor p57; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D017931:DNA Primers; D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D004298:Dopamine