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Molecular Cancer
Published in: Molecular Cancer 1/2013

Open Access 01-12-2013 | Research

PTEN suppresses the oncogenic function of AIB1 through decreasing its protein stability via mechanism involving Fbw7 alpha

Authors: Chunhua Yang, Shujing Li, Miao Wang, Alan K Chang, Ying Liu, Feng Zhao, Liyun Xiao, Lin Han, Dao Wang, Shen Li, Huijian Wu

Published in: Molecular Cancer | Issue 1/2013

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Abstract

Background

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a phosphatase having both protein and lipid phosphatase activities, and is known to antagonize the phosphoinositide 3-kinase/AKT (PI3K/AKT) signaling pathway, resulting in tumor suppression. PTEN is also known to play a role in the regulation of numerous transcription factors. Amplified in breast cancer 1 (AIB1) is a transcriptional coactivator that mediates the transcriptional activities of nuclear receptors and other transcription factors. The present study investigated how PTEN may regulate AIB1, which is amplified and/or overexpressed in many human carcinomas, including breast cancers.

Results

PTEN interacted with AIB1 via its phophatase domain and regulated the transcriptional activity of AIB1 by enhancing the ubiquitin-mediated degradation of AIB1. This process did not appear to require the phosphatase activity of PTEN, but instead, involved the interaction between PTEN and F-box and WD repeat domain-containing 7 alpha (Fbw7α), the E3 ubiquitin ligase involved in the ubiquitination of AIB1. PTEN interacted with Fbw7α via its C2 domain, thereby acting as a bridge between AIB1 and Fbw7α, and this led to enhanced degradation of AIB1, which eventually accounted for its decreased transcriptional activity. At the cell level, knockdown of PTEN in MCF-7 cells promoted cell proliferation. However when AIB1 was also knocked down, knockdown of PTEN had no effect on cell proliferation.

Conclusions

PTEN might act as a negative regulator of AIB1 whereby the association of PTEN with both AIB1 and Fbw7α could lead to the downregulation of AIB1 transcriptional activity, with the consequence of regulating the oncogenic function of AIB1.
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Literature
1.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997, 15 (4): 356-362. 10.1038/ng0497-356CrossRefPubMed
2.
Carracedo A, Alimonti A, Pandolfi PP: PTEN level in tumor suppression: how much is too little?. Cancer Res. 2011, 71 (3): 629-633. 10.1158/0008-5472.CAN-10-2488PubMedCentralCrossRefPubMed
3.
Hollander MC, Blumenthal GM, Dennis PA: PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011, 11 (4): 289-301.CrossRefPubMed
4.
Endersby R, Baker SJ: PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene. 2008, 27 (41): 5416-5430. 10.1038/onc.2008.239CrossRefPubMed
5.
Uzoh CC, Perks CM, Bahl A, Holly JM, Sugiono M, Persad RA: PTEN-mediated pathways and their association with treatment-resistant prostate cancer. BJU Int. 2009, 104 (4): 556-561. 10.1111/j.1464-410X.2009.08411.xCrossRefPubMed
6.
Wu H, Chen Y, Liang J, Shi B, Wu G, Zhang Y, Wang D, Li R, Yi X, Zhang H: Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature. 2005, 438 (7070): 981-987. 10.1038/nature04225CrossRefPubMed
7.
Boruban MC, Altundag K, Kilic GS, Blankstein J: From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures. Eur J Cancer Prev. 2008, 17 (2): 133-138. 10.1097/CEJ.0b013e32811080ceCrossRefPubMed
8.
Saal LH, Gruvberger-Saal SK, Persson C, Lovgren K, Jumppanen M, Staaf J, Jonsson G, Pires MM, Maurer M, Holm K: Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet. 2008, 40 (1): 102-107. 10.1038/ng.2007.39PubMedCentralCrossRefPubMed
9.
Singh G, Chan AM: Post-translational modifications of PTEN and their potential therapeutic implications. Curr Cancer Drug Targets. 2011, 11 (5): 536-547. 10.2174/156800911795655930CrossRefPubMed
10.
11.
Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, Yin Y: Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007, 128 (1): 157-170. 10.1016/j.cell.2006.11.042CrossRefPubMed
12.
Song MS, Carracedo A, Salmena L, Song SJ, Egia A, Malumbres M, Pandolfi PP: Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell. 2011, 144 (2): 187-199. 10.1016/j.cell.2010.12.020PubMedCentralCrossRefPubMed
13.
Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS: AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997, 277 (5328): 965-968. 10.1126/science.277.5328.965CrossRefPubMed
14.
Gojis O, Rudraraju B, Alifrangis C, Krell J, Libalova P, Palmieri C: The role of steroid receptor coactivator-3 (SRC-3) in human malignant disease. Eur J Surg Oncol. 2010, 36 (3): 224-229. 10.1016/j.ejso.2009.08.002CrossRefPubMed
15.
Tanner MM, Grenman S, Koul A, Johannsson O, Meltzer P, Pejovic T, Borg A, Isola JJ: Frequent amplification of chromosomal region 20q12-q13 in ovarian cancer. Clin Cancer Res. 2000, 6 (5): 1833-1839.PubMed
16.
Li AJ, Lerner DL, Gapuzan ME, Karlan BY: AIB1 polymorphisms predict aggressive ovarian cancer phenotype. Cancer Epidemiol Biomarkers Prev. 2005, 14 (12): 2919-2922. 10.1158/1055-9965.EPI-05-0540CrossRefPubMed
17.
Sakaguchi H, Fujimoto J, Sun WS, Tamaya T: Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers. J Steroid Biochem Mol Biol. 2007, 104 (3–5): 237-240.CrossRefPubMed
18.
Henke RT, Haddad BR, Kim SE, Rone JD, Mani A, Jessup JM, Wellstein A, Maitra A, Riegel AT: Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma. Clin Cancer Res. 2004, 10 (18 Pt 1): 6134-6142.CrossRefPubMed
19.
Zhou HJ, Yan J, Luo W, Ayala G, Lin SH, Erdem H, Ittmann M, Tsai SY, Tsai MJ: SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res. 2005, 65 (17): 7976-7983.PubMed
20.
Torres-Arzayus MI, Zhao J, Bronson R, Brown M: Estrogen-dependent and estrogen-independent mechanisms contribute to AIB1-mediated tumor formation. Cancer Res. 2010, 70 (10): 4102-4111. 10.1158/0008-5472.CAN-09-4080PubMedCentralCrossRefPubMed
21.
Torres-Arzayus MI, Font De Mora J, Yuan J, Vazquez F, Bronson R, Rue M, Sellers WR, Brown M: High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell. 2004, 6 (3): 263-274. 10.1016/j.ccr.2004.06.027CrossRefPubMed
22.
Fereshteh MP, Tilli MT, Kim SE, Xu J, O’Malley BW, Wellstein A, Furth PA, Riegel AT: The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice. Cancer Res. 2008, 68 (10): 3697-3706. 10.1158/0008-5472.CAN-07-6702PubMedCentralCrossRefPubMed
23.
Lahusen T, Henke RT, Kagan BL, Wellstein A, Riegel AT: The role and regulation of the nuclear receptor co-activator AIB1 in breast cancer. Breast Cancer Res Treat. 2009, 116 (2): 225-237. 10.1007/s10549-009-0405-2PubMedCentralCrossRefPubMed
24.
25.
Li S, Shang Y: Regulation of SRC family coactivators by post-translational modifications. Cell Signal. 2007, 19 (6): 1101-1112. 10.1016/j.cellsig.2007.02.002CrossRefPubMed
26.
Wu H, Sun L, Zhang Y, Chen Y, Shi B, Li R, Wang Y, Liang J, Fan D, Wu G: Coordinated regulation of AIB1 transcriptional activity by sumoylation and phosphorylation. J Biol Chem. 2006, 281 (31): 21848-21856. 10.1074/jbc.M603772200CrossRefPubMed
27.
Li S, Yang C, Hong Y, Bi H, Zhao F, Liu Y, Ao X, Pang P, Xing X, Chang AK: The transcriptional activity of co-activator AIB1 is regulated by the SUMO E3 Ligase PIAS1. Biol Cell. 2012, 104 (5): 287-296. 10.1111/boc.201100116CrossRefPubMed
28.
Li C, Liang YY, Feng XH, Tsai SY, Tsai MJ, O’Malley BW: Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover. Mol Cell. 2008, 31 (6): 835-849. 10.1016/j.molcel.2008.07.019PubMedCentralCrossRefPubMed
29.
Li X, Lonard DM, Jung SY, Malovannaya A, Feng Q, Qin J, Tsai SY, Tsai MJ, O'Malley BW: The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome. Cell. 2006, 124 (2): 381-392. 10.1016/j.cell.2005.11.037CrossRefPubMed
30.
Mani A, Oh AS, Bowden ET, Lahusen T, Lorick KL, Weissman AM, Schlegel R, Wellstein A, Riegel AT: E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells. Cancer Res. 2006, 66 (17): 8680-8686. 10.1158/0008-5472.CAN-06-0557CrossRefPubMed
31.
Wu RC, Feng Q, Lonard DM, O’Malley BW: SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock. Cell. 2007, 129 (6): 1125-1140. 10.1016/j.cell.2007.04.039CrossRefPubMed
32.
Li C, Ao J, Fu J, Lee DF, Xu J, Lonard D, O’Malley BW: Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene. 2011, 30 (42): 4350-4364. 10.1038/onc.2011.151PubMedCentralCrossRefPubMed
33.
Welcker M, Clurman BE: FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008, 8 (2): 83-93. 10.1038/nrc2290CrossRefPubMed
34.
Chang CJ, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR, Wu H: PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol. 2008, 28 (10): 3281-3289. 10.1128/MCB.00310-08PubMedCentralCrossRefPubMed
35.
Ferrero M, Avivar A, Garcia-Macias MC, de Mora JF: Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation. Cancer Res. 2008, 68 (13): 5450-5459. 10.1158/0008-5472.CAN-07-6433CrossRefPubMed
36.
Keniry M, Parsons R: The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene. 2008, 27 (41): 5477-5485. 10.1038/onc.2008.248CrossRefPubMed
37.
Carracedo A, Pandolfi PP: The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008, 27 (41): 5527-5541. 10.1038/onc.2008.247CrossRefPubMed
38.
39.
40.
41.
Salmena L, Carracedo A, Pandolfi PP: Tenets of PTEN tumor suppression. Cell. 2008, 133 (3): 403-414. 10.1016/j.cell.2008.04.013CrossRefPubMed
42.
Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD: PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell. 2003, 3 (2): 117-130. 10.1016/S1535-6108(03)00021-7CrossRefPubMed
43.
Rahal OM, Simmen RC: PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation. Carcinogenesis. 2010, 31 (8): 1491-1500. 10.1093/carcin/bgq123PubMedCentralCrossRefPubMed
44.
Li AG, Piluso LG, Cai X, Wei G, Sellers WR, Liu X: Mechanistic insights into maintenance of high p53 acetylation by PTEN. Mol Cell. 2006, 23 (4): 575-587. 10.1016/j.molcel.2006.06.028CrossRefPubMed
45.
Lin HK, Hu YC, Lee DK, Chang C: Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells. Mol Endocrinol. 2004, 18 (10): 2409-2423. 10.1210/me.2004-0117CrossRefPubMed
46.
Suo J, Snider SJ, Mills GB, Creighton CJ, Chen AC, Schiff R, Lloyd RE, Chang EC: Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium. Oncogene. 2011, 30 (6): 724-736. 10.1038/onc.2010.445PubMedCentralCrossRefPubMed
47.
Zhou G, Hashimoto Y, Kwak I, Tsai SY, Tsai MJ: Role of the steroid receptor coactivator SRC-3 in cell growth. Mol Cell Biol. 2003, 23 (21): 7742-7755. 10.1128/MCB.23.21.7742-7755.2003PubMedCentralCrossRefPubMed
48.
Karmakar S, Foster EA, Smith CL: Unique roles of p160 coactivators for regulation of breast cancer cell proliferation and estrogen receptor-alpha transcriptional activity. Endocrinology. 2009, 150 (4): 1588-1596. 10.1210/en.2008-1001PubMedCentralCrossRefPubMed
49.
Xing X, Bi H, Chang AK, Zang MX, Wang M, Ao X, Li S, Pan H, Guo Q, Wu H: SUMOylation of AhR modulates its activity and stability through inhibiting its ubiquitination. J Cell Physiol. 2012, 227 (12): 3812-3819. 10.1002/jcp.24092CrossRefPubMed
50.
Li S, Wang M, Ao X, Chang AK, Yang C, Zhao F, Bi H, Liu Y, Xiao L, Wu H: CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-alpha. Oncogene. 2012, 10.1038/onc.2012.518.
51.
Hong Y, Xing X, Li S, Bi H, Yang C, Zhao F, Liu Y, Ao X, Chang AK, Wu H: SUMOylation of DEC1 protein regulates its transcriptional activity and enhances its stability. PLoS One. 2011, 6 (8): e23046- 10.1371/journal.pone.0023046PubMedCentralCrossRefPubMed
Metadata
Title
PTEN suppresses the oncogenic function of AIB1 through decreasing its protein stability via mechanism involving Fbw7 alpha
Authors
Chunhua Yang
Shujing Li
Miao Wang
Alan K Chang
Ying Liu
Feng Zhao
Liyun Xiao
Lin Han
Dao Wang
Shen Li
Huijian Wu
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-12-21

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