A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors.
Loss of the CDK inhibitor p27(KIP1) is widely linked with poor prognosis in human cancer. In Wnt10b-expressing mammary tumors, levels of p27(KIP1) were extremely low; conversely, Wnt10b-null mammary cells expressed high levels of this protein, suggesting Wnt-dependent regulation of p27(KIP1). Interestingly we found that Wnt-induced turnover of p27(KIP1) was independent from classical SCF(SKP2)-mediated degradation in both mouse and human cells. Instead, turnover required Cullin 4A and Cullin 4B, components of an alternative E3 ubiquitin ligase induced in response to active Wnt signaling. We found that CUL4A was a novel Wnt target gene in both mouse and human cells and that CUL4A physically interacted with p27(KIP1) in Wnt-responding cells. We further demonstrated that both Cul4A and Cul4B were required for Wnt-induced p27(KIP1) degradation and S-phase progression. CUL4A and CUL4B are therefore components of a conserved Wnt-induced proteasome targeting (WIPT) complex that regulates p27(KIP1) levels and cell cycle progression in mammalian cells.
Miranda-Carboni
Gustavo A
GA
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Krum
Susan A
SA
Yee
Kathleen
K
Nava
Miguel
M
Deng
Qiming E
QE
Pervin
Shehla
S
Collado-Hidalgo
Alicia
A
Galic
Zoran
Z
Zack
Jerome A
JA
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Lane
Timothy F
TF
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
D044842:Cullin Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D028884:Karyopherins; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear; D044786:S-Phase Kinase-Associated Proteins; D051153:Wnt Proteins; D000097606:Exportin 1 Protein; C114234:CUL4A protein, human; C517832:CUL4B protein, human; C102068:Wnt10b protein, mouse