The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription.
The transcription regulatory oncoprotein c-Myc controls genes involved in cell growth, apoptosis, and oncogenesis. c-Myc is turned over very quickly through the ubiquitin/proteasome pathway. The proteins involved in this process are still unknown. We have found that Skp2 interacts with c-Myc and participates in its ubiquitylation and degradation. The interaction between Skp2 and c-Myc occurs during the G1 to S phase transition of the cell cycle in normal lymphocytes. Surprisingly, Skp2 enhances c-Myc-induced S phase transition and activates c-Myc target genes in a Myc-dependent manner. Further, Myc-induced transcription was shown to be Skp2 dependent, suggesting interdependence between c-Myc and Skp2 in activation of transcription. Moreover, Myc-dependent association of Skp2, ubiquitylated proteins, and subunits of the proteasome to a c-Myc target promoter was demonstrated in vivo. The results suggest that Skp2 is a transcriptional cofactor for c-Myc and indicates a close relationship between transcription activation and transcription factor ubiquitination.
von der Lehr
Natalie
N
Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden.
Johansson
Sara
S
Wu
Siqin
S
Bahram
Fuad
F
Castell
Alina
A
Cetinkaya
Cihan
C
Hydbring
Per
P
Weidung
Ingrid
I
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Söderberg
Ola
O
Kerppola
Tom K
TK
Larsson
Lars-Gunnar
LG
D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins; D015533:Transcriptional Activation / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
C080336:CCND2 protein, human; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; C489427:MYC protein, human; D009097:Multienzyme Complexes; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex