A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors

Gustavo A. Miranda-Carboni, Susan A. Krum, Kathleen Yee, Miguel Nava, Qiming E. Deng, Shehla Pervin, Alicia Collado-Hidalgo, Zoran Galić, Jerome A. Zack, Keiko Nakayama, Keiichi I. Nakayama, Timothy F. Lane

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59 Citations (Scopus)

Abstract

Loss of the CDK inhibitor p27KIP1 is widely linked with poor prognosis in human cancer. In Wnt10b-expressing mammary tumors, levels of p27KIP1 were extremely low; conversely, Wnt10b-null mammary cells expressed high levels of this protein, suggesting Wnt-dependent regulation of p27KIP1. Interestingly we found that Wnt-induced turnover of p27 KIP1 was independent from classical SCFSKP2-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 p27KIP1 in Wnt-responding cells. We further demonstrated that both Cul4A and Cul4B were required for Wnt-induced p27KIP1 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.

Original languageEnglish
Pages (from-to)3121-3134
Number of pages14
JournalGenes and Development
Volume22
Issue number22
DOIs
Publication statusPublished - 2008 Nov 15

Keywords

  • Basal-like breast cancer
  • Cdkn1b
  • Mammary progenitor cells
  • Mammary stem cell (MSC)
  • Reprogramming
  • Wnt-induced proteasome targeting (WIPT)

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Miranda-Carboni, G. A., Krum, S. A., Yee, K., Nava, M., Deng, Q. E., Pervin, S., Collado-Hidalgo, A., Galić, Z., Zack, J. A., Nakayama, K., Nakayama, K. I., & Lane, T. F. (2008). A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors. Genes and Development, 22(22), 3121-3134. https://doi.org/10.1101/gad.1692808