p27(Kip1) signaling: Transcriptional and post-translational regulation.
p27(Kip1) is an inhibitor of a broad spectrum of cyclin-dependent kinases (CDKs), and the loss of a single p27(Kip1) allele is thereby sufficient to increase tumor incidence via CDK-mediated cell cycle entry. As such, down-regulation of p27(Kip1) protein levels, in particular nuclear expressed p27(Kip1), is implicated in both disease progression and poor prognosis in a variety of cancers. p27(Kip1) expression is positively regulated by the transcription factor MENIN, and inhibited by oncogenic transcription factors MYC and PIM. However, regulation of p27(Kip1) protein expression and function is predominantly through post-translational modifications that alter both the cellular localization and the extent of E3 ubiquitin ligase-mediated degradation. Phosphorylation of p27(Kip1) at Thr(187) and Ser(10) is a prerequisite for its degradation via the E3 ubiquitin ligases SKP2 (nuclear) and KPC (cytoplasmic), respectively. Additionally, Ser(10) phosphorylated p27(Kip1) is predominantly localized in the cytoplasm due to the nuclear export protein CRM1. Another E3 ubiquitin ligase, PIRH2, degrades p27(Kip1) in both the cytoplasm and nucleus independent of phosphorylation state. As such, inhibition of cell cycle entry and progression in a variety of cancers may be achieved with therapies designed to correct p27(Kip1) localization and/or block its degradation.
School of Science and Health, University of Western Sydney, Australia.
Su Su Thae
SS
Hnit
School of Science and Health, University of Western Sydney, Australia.
Chanlu
C
Xie
Central Clinical School and Charles Perkins Centre, The University of Sydney and Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia.
Mu
M
Yao
Origins of Cancer Program, Centenary Institute, Camperdown, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
Jeff
J
Holst
National Institute of Complementary Medicine, University of Western Sydney, Australia.
Alan
A
Bensoussan
School of Medicine, University of Western Sydney, Australia.
Paul
P
De Souza
Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. Electronic address: lee171@163.com.
Zhong
Z
Li
School of Science and Health, University of Western Sydney, Australia; Central Clinical School and Charles Perkins Centre, The University of Sydney and Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia; School of Medicine, University of Western Sydney, Australia. Electronic address: q.dong@uws.edu.au.
Qihan
Q
Dong
D002453:Cell Cycle / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
C105373:MEN1 protein, human; C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C574376:RNF123 protein, human; D044767:Ubiquitin-Protein Ligases; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D046988:Proteasome Endopeptidase Complex
CRM1; KPC; MYC; PIRH2; SKP2; p27(Kip1)