- Open Access
p27KIP1phosphorylation by PKB/Akt leads to poor breast cancer prognosis
Breast Cancer Research volume 5, Article number: 162 (2003)
Three papers published concurrently in the October issue of Nature Medicine have demonstrated new links between mitogenic cytokine signalling and the cell cycle inhibitor p27KIP1, and have elucidated how this link may contribute to breast cancer patient prognosis [1–3].
Cell cycle control occurs through cyclin binding to the cyclin-dependent kinases (CDKs) that stimulate G1 progression . p27KIP1 is a member of the kinase inhibitor protein (KIP) family that inhibit cell cycle progression by binding to cyclin-CDK complexes . In cancers where protein kinase B (PKB)/Akt is constitutively activated by upstream oncogenes, Akt decreases p27KIP1 by increasing proteolysis and reducing transcription .
These three articles describe a third way in which Akt resists G1 arrest, namely by a p27KIP1 phosphorylation that impairs nuclear import and prevents its inhibition of cyclin-CDK complexes. The authors of these studies conclude that exclusion of p27KIP1 from the nucleus leads to a poor patient outcome in breast cancer [1–3].
p27KIP1phosphorylation leads to cytoplasmic localisation
Wild type and constitutively active Akt were both shown to phosphorylate p27KIP1 at threonine157, leading to cytoplasmic localisation of p27KIP1. Blockade of Akt activation by the phosphatidyl inositol 3'-kinase (PI3K) inhibitor LY294002, or transfection with the mutant p27KIP1-T157A, led to nuclear p27KIP1 localisation. Constitutively active Akt prevented wild type p27KIP1, but not p27KIP1-T157A, from causing G1 arrest.
In two of the studies it was reported that approximately 40% of primary breast tumours displayed cytoplasmic p27KIP1 staining [1, 3]. The presence of cytoplasmic p27KIP1 in human breast cancers was highly correlated with Akt activation. The best prognostic subgroup of breast tumours had strong, exclusively nuclear p27KIP1 staining, while cancers with lower expression levels, but cytoplasmic localisation, had the worst survival rates.
The data indicate that p27KIP1 normally acts as a tumour suppressor protein, but that the oncogenic activation of Akt leads to mislocation of p27KIP1 to the cytoplasm where it is unable to inhibit cell cycle proteins. The study indicates that cytoplasmic location of p27KIP1 in breast tumours is a prognostic indicator and that the Akt pathway may be a good target for anti-cancer therapy.
p27KIP1 is an inhibitor of cell cycle progression that is rarely mutated or silenced in cancers. The Nature Medicine articles demonstrate that p27KIP1 depends on a nuclear location to perform its cell cycle inhibitory function and that Akt phosphorylates p27KIP1 leading to its mislocalisation in the cytoplasm [1–3].
Akt lies downstream of PI3K and the growth factor receptors epidermal growth factor receptor (EGFR) and ErbB2, which act as oncogenes in numerous cancers . This means that Akt is commonly activated in many forms of cancer . All three of these studies confirm that the action of Akt on p27KIP1 localisation appears crucial to breast tumour progression [1–3]. There is evidence that Akt can also exclude nuclear presence of another cell cycle inhibitor, p21CIP1 . It will be interesting to see whether the cellular location of p21CIP1 will add to the prognostic information given by p27KIP1 in cancers.
Finally, the articles suggest new therapeutic opportunities in targeting Akt or the p27KIP1 phosphorylation site to relocate p27KIP1 to the nucleus and improve the long-term prognosis of breast cancer patients in whom this important cell cycle regulator is mislocated.
= cyclin-dependant kinase
= kinase inhibitor protein
= protein kinase B
= phosphatidyl inositol 3'-kinase.
Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM: PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002, 8: 1153-1160. 10.1038/nm761. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr596.asp#liang
Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL: PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nat Med. 2002, 8: 1145-1152. 10.1038/nm759. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr596.asp#shin
Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M: Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002, 8: 1136-1144. 10.1038/nm762. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr596.asp#viglietto
Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999, 13: 1501-1512.
Slingerland JM, Hengst L, Pan CH, Alexander D, Stampfer MR, Reed SI: A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells. Mol Cell Biol. 1994, 14: 3683-3694.
Slingerland J, Pagano M: Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol. 2000, 183: 10-17. 10.1002/(SICI)1097-4652(200004)183:1<10::AID-JCP2>3.3.CO;2-9.
Sun H, Lesche R, Li DM, Liliental J, Zhang JH, Gao J, Gavrilova N, Mueller B, Liu X, Wu H: PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1999, 96: 6199-6204. 10.1073/pnas.96.11.6199.
Testa JR, Bellacosa A: AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001, 98: 10983-10985. 10.1073/pnas.211430998.
Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC: Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 2001, 3: 245-252. 10.1038/35060032.
This article is based on papers highlighted by Faculty of 1000 http://www.facultyof1000.com/start.asp, a web-based literature awareness service. Faculty of 1000 evaluations available for articles cited in this report may be viewed at: http://breast-cancer-research.com/reports/bcr596.asp
About this article
Cite this article
Clarke, R.B. p27KIP1phosphorylation by PKB/Akt leads to poor breast cancer prognosis. Breast Cancer Res 5, 162 (2003) doi:10.1186/bcr596
- Inhibit Cell Cycle Progression
- Breast Tumour Progression
- Receptor Epidermal Growth Factor Receptor
- Inhibit Cell Cycle Protein
- Poor Breast Cancer Prognosis