A large amount of data supports the view that PTEN is a bona fide tumor suppressor gene. However, recent evidence suggests that derailment of cellular localization and expression levels of functional nonmutated PTEN is a determining force in inducing abnormal cellular and tissue outcomes. As the cellular mechanisms that regulate normal PTEN enzymatic activity resolve, it is evident that deregulation of these mechanisms can alter cellular processes and tissue architecture and ultimately lead to oncogenic transformation. Here we discuss PTEN ubiquitination, PTEN complex formation with components of the adherens junction, PTEN nuclear localization, and microRNA regulation of PTEN as essential regulatory mechanisms that determine PTEN function independent of gene mutations and epigenetic events. 1. PTEN: A Unique Dual-Specificity Phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten)/MMAC (mutated in multiple advanced cancers) has been identified simultaneously by two research groups as a candidate tumor suppressor gene located at 10q23 and encoding 403 amino acids [1, 2]. Another group identified the same gene in the search for new dual-specific phosphatases and named it TEP-1 (TGF-β regulated and epithelial cell-enriched phosphatase) [3]. PTEN is one of the most common targets of mutation in human cancer, with a mutation frequency approaching that of the tumor suppressor gene p53, and it is also mutated in inherited cancer predisposition disorders. PTEN belongs to the protein tyrosine phosphatase family with phosphatase activity on both lipids and proteins. PTEN’s lipid phosphatase catalyzes the conversion of phosphatidylinositol-(3,4,5)-triphosphate (PIP3) to phosphatidylinositol-4,5-bisphosphate (PIP2) [4, 5] and plays an important role in the PI3K pathway by catalyzing degradation of PIP3 generated by PI3K. This inhibits PI3K downstream targets, mainly PKB-Akt [6–10]. It should be noted, however, that lipid phosphatase attenuated or inactive PTEN mutants have been reported to still retain some tumor suppressing properties [11–15]. So far there is no report of redundancy for PTEN function, which could explain the high frequency with which PTEN inactivation is selected during tumor development [16]. By virtue of PTEN’s ability to attenuate and control the extent of PI3K signaling, PTEN influences many cellular functions, including cell growth, survival, proliferation, and metabolism [8]. PTEN contributes to cell cycle regulation by blocking cells entering the S-phase of the cell cycle and by upregulation of p27kip1, which is
References
[1]
J. Li, C. Yen, D. Liaw et al., “PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer,” Science, vol. 275, no. 5308, pp. 1943–1947, 1997.
[2]
P. A. Steck, M. A. Pershouse, S. A. Jasser et al., “Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers,” Nature Genetics, vol. 15, no. 4, pp. 356–362, 1997.
[3]
D. M. Li and H. Sun, “TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β,” Cancer Research, vol. 57, no. 11, pp. 2124–2129, 1997.
[4]
S. J. Leevers, B. Vanhaesebroeck, and M. D. Waterfield, “Signalling through phosphoinositide 3-kinases: the lipids take centre stage,” Current Opinion in Cell Biology, vol. 11, no. 2, pp. 219–225, 1999.
[5]
T. Maehama and J. E. Dixon, “The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate,” Journal of Biological Chemistry, vol. 273, no. 22, pp. 13375–13378, 1998.
[6]
P. L. M. Dahia, “PTEN, a unique tumor suppressor gene,” Endocrine-Related Cancer, vol. 7, no. 2, pp. 115–129, 2000.
[7]
A. Hlobilková, J. Knillová, J. Bártek, J. Lukás, and Z. Kolár, “The mechanism of action of the tumour suppressor gene PTEN,” Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, vol. 147, no. 1, pp. 19–25, 2003.
[8]
S. Zhang and D. Yu, “PI(3)king apart PTEN's role in cancer,” Clinical Cancer Research, vol. 16, no. 17, pp. 4325–4330, 2010.
[9]
V. Stambolic, A. Suzuki, J. L. De la Pompa et al., “Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN,” Cell, vol. 95, no. 1, pp. 29–39, 1998.
[10]
H. Sun, R. Lesche, D. M. Li et al., “PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 11, pp. 6199–6204, 1999.
[11]
C. Blanco-Aparicio, O. Renner, J. F. M. Leal, and A. Carnero, “PTEN, more than the AKT pathway,” Carcinogenesis, vol. 28, no. 7, pp. 1379–1386, 2007.
[12]
M. M. Georgescu, K. H. Kirsch, P. Kaloudis, H. Yang, N. P. Pavletich, and H. Hanafusa, “Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor,” Cancer Research, vol. 60, no. 24, pp. 7033–7038, 2000.
[13]
J. J. Gildea, M. Herlevsen, M. A. Harding et al., “PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatase activity,” Oncogene, vol. 23, no. 40, pp. 6788–6797, 2004.
[14]
D. Koul, S. A. Jasser, Y. Lu et al., “Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity,” Oncogene, vol. 21, no. 15, pp. 2357–2364, 2002.
[15]
D. Maier, G. Jones, X. Li et al., “The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells,” Cancer Research, vol. 59, no. 21, pp. 5479–5482, 1999.
[16]
M. L. Sulis and R. Parsons, “PTEN: from pathology to biology,” Trends in Cell Biology, vol. 13, no. 9, pp. 478–483, 2003.
[17]
L. P. Weng, J. L. Brown, and C. Eng, “PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways,” Human Molecular Genetics, vol. 10, no. 3, pp. 237–242, 2001.
[18]
A. Radu, V. Neubauer, T. Akagi, H. Hanafusa, and M. M. Georgescu, “PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1,” Molecular and Cellular Biology, vol. 23, no. 17, pp. 6139–6149, 2003.
[19]
F. B. Furnari, H. J. Su Huang, and W. K. Cavenee, “The phosphoinositol phosphatase activity of PTEN mediates a serum- sensitive G1 growth arrest in glioma cells,” Cancer Research, vol. 58, no. 22, pp. 5002–5008, 1998.
[20]
M. Tamura, J. Gu, K. Matsumoto, S. I. Aota, R. Parsons, and K. M. Yamada, “Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN,” Science, vol. 280, no. 5369, pp. 1614–1617, 1998.
[21]
M. Tamura, J. Gu, E. H. J. Danen, T. Takino, S. Miyamoto, and K. M. Yamada, “PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway,” Journal of Biological Chemistry, vol. 274, no. 29, pp. 20693–20703, 1999.
[22]
M. Tamura, J. Gu, T. Takino, and K. M. Yamada, “Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130(Cas),” Cancer Research, vol. 59, no. 2, pp. 442–449, 1999.
[23]
M. Tamura, J. Gu, H. Tran, and K. M. Yamada, “PTEN gene and integrin signaling in cancer,” Journal of the National Cancer Institute, vol. 91, no. 21, pp. 1820–1828, 1999.
[24]
J. A. Hobert and C. Eng, “PTEN hamartoma tumor syndrome: an overview,” Genetics in Medicine, vol. 11, no. 10, pp. 687–694, 2009.
[25]
M. C. Hollander, G. M. Blumenthal, and P. A. Dennis, “PTEN loss in the continuum of common cancers, rare syndromes and mouse models,” Nature Reviews Cancer, vol. 11, no. 4, pp. 289–301, 2011.
[26]
N. M. Monte, K. A. Webster, D. Neuberg, G. R. Dressler, and G. L. Mutter, “Joint loss of PAX2 and PTEN expression in endometrial precancers and cancer,” Cancer Research, vol. 70, no. 15, pp. 6225–6232, 2010.
[27]
F. Meng, R. Henson, H. Wehbe-Janek, K. Ghoshal, S. T. Jacob, and T. Patel, “MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer,” Gastroenterology, vol. 133, no. 2, pp. 647–658, 2007.
[28]
N. Amodio, M. Scrima, L. Palaia et al., “Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas,” American Journal of Pathology, vol. 177, no. 5, pp. 2622–2634, 2010.
[29]
J. C. Soria, H. Y. Lee, J. I. Lee et al., “Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation,” Clinical Cancer Research, vol. 8, no. 5, pp. 1178–1184, 2002.
[30]
C. J. Marsit, S. Zheng, K. Aldape et al., “PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration,” Human Pathology, vol. 36, no. 7, pp. 768–776, 2005.
[31]
Y. E. Whang, X. Wu, H. Suzuki et al., “Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 9, pp. 5246–5250, 1998.
[32]
L. Salmena, A. Carracedo, and P. P. Pandolfi, “Tenets of PTEN tumor suppression,” Cell, vol. 133, no. 3, pp. 403–414, 2008.
[33]
K. Podsypanina, L. H. Ellenson, A. Nemes et al., “Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 4, pp. 1563–1568, 1999.
[34]
A. Suzuki, J. L. De La Pompa, V. Stambolic et al., “High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice,” Current Biology, vol. 8, no. 21, pp. 1169–1178, 1998.
[35]
L. C. Trotman, M. Niki, Z. A. Dotan et al., “Pten dose dictates cancer progression in the prostate,” PLoS Biology, vol. 1, no. 3, article E59, 2003.
[36]
A. Di Cristofano, B. Pesce, C. Cordon-Cardo, and P. P. Pandolfi, “Pten is essential for embryonic development and tumour suppression,” Nature Genetics, vol. 19, no. 4, pp. 348–355, 1998.
[37]
A. Alimonti, A. Carracedo, J. G. Clohessy et al., “Subtle variations in Pten dose determine cancer susceptibility,” Nature Genetics, vol. 42, no. 5, pp. 454–458, 2010.
[38]
K. Stemke-Hale, A. M. Gonzalez-Angulo, A. Lluch et al., “An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer,” Cancer Research, vol. 68, no. 15, pp. 6084–6091, 2008.
[39]
B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, and G. B. Mills, “Exploiting the PI3K/AKT pathway for cancer drug discovery,” Nature Reviews Drug Discovery, vol. 4, no. 12, pp. 988–1004, 2005.
[40]
J. Brugge, M. C. Hung, and G. B. Mills, “A new mutational aktivation in the PI3K pathway,” Cancer Cell, vol. 12, no. 2, pp. 104–107, 2007.
[41]
E. K. Yim, G. Peng, H. Dai et al., “Rak functions as a tumor suppressor by regulating PTEN protein stability and function,” Cancer Cell, vol. 15, no. 4, pp. 304–314, 2009.
[42]
F. Vazquez, S. Ramaswamy, N. Nakamura, and W. R. Sellers, “Phosphorylation of the PTEN tail regulates protein stability and function,” Molecular and Cellular Biology, vol. 20, no. 14, pp. 5010–5018, 2000.
[43]
Z. M. Sheng, A. Marchetti, F. Buttitta et al., “Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas,” British Journal of Cancer, vol. 73, no. 2, pp. 144–147, 1996.
[44]
T. Mund and H. R. B. Pelham, “Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 25, pp. 11429–11434, 2010.
[45]
L. C. Trotman, X. Wang, A. Alimonti et al., “Ubiquitination regulates PTEN nuclear import and tumor suppression,” Cell, vol. 128, no. 1, pp. 141–156, 2007.
[46]
X. Wang, L. C. Trotman, T. Koppie et al., “NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN,” Cell, vol. 128, no. 1, pp. 129–139, 2007.
[47]
F. Fouladkou, T. Landry, H. Kawabe et al., “The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 25, pp. 8585–8590, 2008.
[48]
X. R. Cao, N. L. Lill, N. Boase et al., “Nedd4 controls animal growth by regulating IGF-1 signaling,” Science signaling, vol. 1, no. 38, article ra5, 2008.
[49]
C. Van Themsche, V. Leblanc, S. Parent, and E. Asselin, “X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization,” Journal of Biological Chemistry, vol. 284, no. 31, pp. 20462–20466, 2009.
[50]
Q. L. Deveraux, R. Takahashi, G. S. Salvesen, and J. C. Reed, “X-linked IAP is a direct inhibitor of cell-death proteases,” Nature, vol. 388, no. 6639, pp. 300–304, 1997.
[51]
A. D. Schimmer, S. Dalili, R. A. Batey, and S. J. Riedl, “Targeting XIAP for the treatment of malignancy,” Cell Death and Differentiation, vol. 13, no. 2, pp. 179–188, 2006.
[52]
A. Gericke, M. Munson, and A. H. Ross, “Regulation of the PTEN phosphatase,” Gene, vol. 374, no. 1-2, pp. 1–9, 2006.
[53]
M. Yilmaz and G. Christofori, “Mechanisms of motility in metastasizing cells,” Molecular Cancer Research, vol. 8, no. 5, pp. 629–642, 2010.
[54]
Y. Zhang, B. Ma, and Q. Fan, “Mechanisms of breast cancer bone metastasis,” Cancer Letters, vol. 292, no. 1, pp. 1–7, 2010.
[55]
M. Mareel, T. Boterberg, V. No？ et al., “E-cadherin/catenin/cytoskeleton complex: a regulator of cancer invasion,” Journal of Cellular Physiology, vol. 173, no. 2, pp. 271–274, 1997.
[56]
X. Wu, K. Hepner, S. Castelino-Prabhu et al., “Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 8, pp. 4233–4238, 2000.
[57]
M. C. Subauste, P. Nalbant, E. D. Adamson, and K. M. Hahn, “Vinculin controls PTEN protein level by maintaining the interaction of the adherens junction protein β-catenin with the scaffolding protein MAGI-2,” Journal of Biological Chemistry, vol. 280, no. 7, pp. 5676–5681, 2005.
[58]
T. Tolkacheva, M. Boddapati, A. Sanfiz, K. Tsuchida, A. C. Kimmelman, and A. M. L. Chan, “Regulation of PTEN binding to MAGI-2 by two putative phosphorylation sites at threonine 382 and 383,” Cancer Research, vol. 61, no. 13, pp. 4985–4989, 2001.
[59]
Y. Hu, Z. Li, L. Guo et al., “MAGI-2 Inhibits cell migration and proliferation via PTEN in human hepatocarcinoma cells,” Archives of Biochemistry and Biophysics, vol. 467, no. 1, pp. 1–9, 2007.
[60]
J. H. Zuo, et al., “Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin,” Journal of Cellular Biochemistry, vol. 112, no. 9, pp. 2508–2517, 2011.
[61]
B. Fingleton, C. C. Lynch, T. Vargo-Gogola, and L. M. Matrisian, “Cleavage of E-cadherin by matrix metalloproteinase-7 promotes cellular proliferation in nontransformed cell lines via activation of RhoA,” Journal of Oncology, vol. 2010, Article ID 530745, 11 pages, 2010.
[62]
L. Mohamet, M. L. Lea, and C. M. Ward, “Abrogation of E-cadherin-mediated cellular aggregation allows proliferation of pluripotent mouse embryonic stem cells in shake flask bioreactors,” PLoS ONE, vol. 5, no. 9, article e12921, 2010.
[63]
J. C. M. de Freitas Junior, B. D. R. D. Silva, W. F. de Souza, W. M. de Araújo, E. S. F. W. Abdelhay, and J. A. Morgado-Díaz, “Inhibition of N-linked glycosylation by tunicamycin induces E-cadherin-mediated cell-cell adhesion and inhibits cell proliferation in undifferentiated human colon cancer cells,” Cancer Chemotherapy and Pharmacology, vol. 68, no. 1, pp. 227–238, 2011.
[64]
S. Rachagani, S. Senapati, S. Chakraborty et al., “Activated Kras G12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin,” British Journal of Cancer, vol. 104, no. 6, pp. 1038–1048, 2011.
[65]
R. M. Bremnes, R. Veve, F. R. Hirsch, and W. A. Franklin, “The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis,” Lung Cancer, vol. 36, no. 2, pp. 115–124, 2002.
[66]
M.-T. Lau, C. Klausen, and P. C. K. Leung, “E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via beta-catenin-Egr1-mediated PTEN expression,” Oncogene, vol. 30, no. 24, pp. 2753–2766, 2011.
[67]
M. V. Fournier, J. E. Fata, K. J. Martin, P. Yaswen, and M. J. Bissell, “Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells,” Cancer Research, vol. 69, no. 10, pp. 4545–4552, 2009.
[68]
L. Kotelevets, J. Van Hengel, E. Bruyneel, M. Mareel, F. Van Roy, and E. Chastre, “The lipid phosphatase activity of PTEN is critical for stabilizing intercellular junctions and reverting invasiveness,” Journal of Cell Biology, vol. 155, no. 7, pp. 1129–1135, 2001.
[69]
N. B. Adey, L. Huang, P. A. Ormonde et al., “Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and stimulates PDZ binding,” Cancer Research, vol. 60, no. 1, pp. 35–37, 2000.
[70]
Y. Wu, D. Dowbenko, S. Spencer et al., “Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase,” Journal of Biological Chemistry, vol. 275, no. 28, pp. 21477–21485, 2000.
[71]
L. Kotelevets, J. Van Hengel, E. Bruyneel, M. Mareel, F. Van Roy, and E. Chastre, “Implication of the MAGI-1b/PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness,” FASEB Journal, vol. 19, no. 1, pp. 115–117, 2005.
[72]
X. Peng, L. E. Cuff, C. D. Lawton, and K. A. DeMali, “Vinculin regulates cell-surface E-cadherin expression by binding to β-catenin,” Journal of Cell Science, vol. 123, no. 4, pp. 567–577, 2010.
[73]
T. Virolle, E. D. Adamson, V. Baron et al., “The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling,” Nature Cell Biology, vol. 3, no. 12, pp. 1124–1128, 2001.
[74]
T. Sano, H. Lin, X. Chen et al., “Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis,” Cancer Research, vol. 59, no. 8, pp. 1820–1824, 1999.
[75]
A. Perren, L. P. Weng, A. H. Boag et al., “Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast,” American Journal of Pathology, vol. 155, no. 4, pp. 1253–1260, 1999.
[76]
O. Gimm, A. Perren, L. P. Weng et al., “Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors,” American Journal of Pathology, vol. 156, no. 5, pp. 1693–1700, 2000.
[77]
S. Semba, S. Satake, M. Matsushita, and H. Yokozaki, “Phosphatase activity of nuclear PTEN is required for CDX2-mediated intestinal differentiation of gastric carcinoma,” Cancer Letters, vol. 274, no. 1, pp. 143–150, 2009.
[78]
D. C. Whiteman, X. P. Zhou, M. C. Cummings, S. Pavey, N. K. Hayward, and C. Eng, “Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma,” International Journal of Cancer, vol. 99, no. 1, pp. 63–67, 2002.
[79]
K. S. Jang, Y. S. Song, S. H. Jang et al., “Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma,” Histopathology, vol. 56, no. 2, pp. 229–239, 2010.
[80]
M. E. Ginn-Pease and C. Eng, “Increased nuclear phosphatase and tensin homologue deleted on chromosome 10 is associated with G0-G1 in MCF-7 cells,” Cancer Research, vol. 63, no. 2, pp. 282–286, 2003.
[81]
J. H. Chung and C. Eng, “Nuclear-cytoplasmic partitioning of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) differentially regulates the cell cycle and apoptosis,” Cancer Research, vol. 65, no. 18, pp. 8096–8100, 2005.
[82]
A. I. Jacob, T. Romigh, K. A. Waite, and C. Eng, “Nuclear PTEN levels and G2 progression in melanoma cells,” Melanoma research, vol. 19, no. 4, pp. 203–210, 2009.
[83]
M. Tachibana, M. Shibakita, S. Ohno et al., “Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma,” Cancer, vol. 94, no. 7, pp. 1955–1960, 2002.
[84]
X. P. Zhou, A. Loukola, R. Salovaara et al., “PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers,” American Journal of Pathology, vol. 161, no. 2, pp. 439–447, 2002.
[85]
S. M. Planchon, K. A. Waite, and C. Eng, “The nuclear affairs of PTEN,” Journal of Cell Science, vol. 121, no. 3, pp. 249–253, 2008.
[86]
F. Liu, S. Wagner, R. B. Campbell, J. A. Nickerson, C. A. Schiffer, and A. H. Ross, “PTEN enters the nucleus by diffusion,” Journal of Cellular Biochemistry, vol. 96, no. 2, pp. 221–234, 2005.
[87]
T. Boulikas, “Nuclear localization signals (NLS),” Critical Reviews in Eukaryotic Gene Expression, vol. 3, no. 3, pp. 193–227, 1993.
[88]
R. Peters, “Fluorescence microphotolysis to measure nucleocytoplasmic transport and intracellular mobility,” Biochimica et Biophysica Acta, vol. 864, no. 3-4, pp. 305–359, 1986.
[89]
S. Kuersten, M. Ohno, and I. W. Mattaj, “Nucleocytoplasmic transport: ran, beta and beyond,” Trends in Cell Biology, vol. 11, no. 12, pp. 497–503, 2001.
[90]
A. Gil, A. Andrés-Pons, E. Fernandez et al., “Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs,” Molecular Biology of the Cell, vol. 17, no. 9, pp. 4002–4013, 2006.
[91]
M. H. Mossink, A. Van Zon, R. J. Scheper, P. Sonneveld, and E. A. C. Wiemer, “Vaults: a ribonucleoprotein particle involved in drug resistance?” Oncogene, vol. 22, no. 47, pp. 7458–7467, 2003.
[92]
Y. Zhenbao, N. Fotouhi-Ardakani, L. Wu et al., “PTEN associates with the vault particles in HeLa cells,” Journal of Biological Chemistry, vol. 277, no. 43, pp. 40247–40252, 2002.
[93]
J. Torres and R. Pulido, “The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation,” Journal of Biological Chemistry, vol. 276, no. 2, pp. 993–998, 2001.
[94]
M. M. Georgescu, K. H. Kirsch, T. Akagi, T. Shishido, and H. Hanafusa, “The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 18, pp. 10182–10187, 1999.
[95]
J. Torres, J. Rodriguez, M. P. Myers et al., “Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3. Implications for the control of protein stability and PTEN-protein interactions,” Journal of Biological Chemistry, vol. 278, no. 33, pp. 30652–30660, 2003.
[96]
M. Raftopoulou, S. Etienne-Manneville, A. Self, S. Nicholls, and A. Hall, “Regulation of cell migration by the C2 domain of the tumor suppressor PTEN,” Science, vol. 303, no. 5661, pp. 1179–1181, 2004.
[97]
L. Odriozola, G. Singh, T. Hoang, and A. M. Chan, “Regulation of PTEN activity by its carboxyl-terminal autoinhibitory domain,” Journal of Biological Chemistry, vol. 282, no. 32, pp. 23306–23315, 2007.
[98]
C. J. Chang, D. J. Mulholland, B. Valamehr, S. Mosessian, W. R. Sellers, and H. Wu, “PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression,” Molecular and Cellular Biology, vol. 28, no. 10, pp. 3281–3289, 2008.
[99]
J. L. Liu, Z. Mao, T. A. LaFortune et al., “Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade,” Cancer Research, vol. 67, no. 22, pp. 11054–11063, 2007.
[100]
J.-L. Liu, Z. Mao, G. E. Gallick, and W. K.A. Yung, “AMPK/TSC2/mTOR-signaling intermediates are not necessary for LKB1-mediated nuclear retention of PTEN tumor suppressor,” Neuro-Oncology, vol. 13, no. 2, pp. 184–194, 2011.
[101]
M. S. Song, A. Carracedo, L. Salmena et al., “Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner,” Cell, vol. 144, no. 2, pp. 187–199, 2011.
[102]
T. Cardozo and M. Pagano, “The SCF ubiquitin ligase: insights into a molecular machine,” Nature Reviews Molecular Cell Biology, vol. 5, no. 9, pp. 739–751, 2004.
[103]
J. M. Peters, “The anaphase promoting complex/cyclosome: a machine designed to destroy,” Nature Reviews Molecular Cell Biology, vol. 7, no. 9, pp. 644–656, 2006.
[104]
J. Pines, “Mitosis: a matter of getting rid of the right protein at the right time,” Trends in Cell Biology, vol. 16, no. 1, pp. 55–63, 2006.
[105]
M. Sullivan and D. O. Morgan, “Finishing mitosis, one step at a time,” Nature Reviews Molecular Cell Biology, vol. 8, no. 11, pp. 894–903, 2007.
[106]
S. M. Hammond, “RNAi, microRNAs, and human disease,” Cancer Chemotherapy and Pharmacology, vol. 58, pp. s63–s68, 2006.
[107]
V. Ambros, “MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing,” Cell, vol. 113, no. 6, pp. 673–676, 2003.
[108]
S. Bagga, “Posttransplant lymphoproliferative disease in a pediatric patient as seen on PET/CT scan,” Clinical Nuclear Medicine, vol. 32, no. 7, pp. 553–554, 2007.
[109]
D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004.
[110]
K. K. H. Farh, A. Grimson, C. Jan et al., “The widespread impact of mammalian microRNAs on mRNA repression and evolution,” Science, vol. 310, no. 5755, pp. 1817–1821, 2005.
[111]
D. S. Schwarz, G. Hutvágner, T. Du, Z. Xu, N. Aronin, and P. D. Zamore, “Asymmetry in the assembly of the RNAi enzyme complex,” Cell, vol. 115, no. 2, pp. 199–208, 2003.
[112]
T. Li, D. Li, J. Sha, P. Sun, and Y. Huang, “MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells,” Biochemical and Biophysical Research Communications, vol. 383, no. 3, pp. 280–285, 2009.
[113]
Z. Liang, H. Wu, S. Reddy et al., “Blockade of invasion and metastasis of breast cancer cells via targeting CXCR4 with an artificial microRNA,” Biochemical and Biophysical Research Communications, vol. 363, no. 3, pp. 542–546, 2007.
[114]
L. X. Yan, X. F. Huang, Q. Shao et al., “MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis,” RNA, vol. 14, no. 11, pp. 2348–2360, 2008.
[115]
S. F. Tavazoie, C. Alarcón, T. Oskarsson et al., “Endogenous human microRNAs that suppress breast cancer metastasis,” Nature, vol. 451, no. 7175, pp. 147–152, 2008.
[116]
S. Valastyan, F. Reinhardt, N. Benaich et al., “A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis,” Cell, vol. 137, no. 6, pp. 1032–1046, 2009.
[117]
X. F. Li, P. J. Yan, and Z. M. Shao, “Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer,” Oncogene, vol. 28, no. 44, pp. 3937–3948, 2009.
[118]
J. G. Zhang, J. J. Wang, F. Zhao, Q. Liu, K. Jiang, and G. H. Yang, “MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC),” Clinica Chimica Acta, vol. 411, no. 11-12, pp. 846–852, 2011.
[119]
X. Ma, M. Kumar, S. N. Choudhury et al., “Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 25, pp. 10144–10149, 2011.
[120]
L. Qi, J. Bart, L. P. Tan et al., “Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma,” BMC Cancer, vol. 9, article 163, 2009.
[121]
M. Folini, P. Gandellini, N. Longoni et al., “miR-21: an oncomir on strike in prostate cancer,” Molecular Cancer, vol. 9, article 12, 2010.
[122]
H. Yang, W. Kong, L. He et al., “MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN,” Cancer Research, vol. 68, no. 2, pp. 425–433, 2008.
[123]
A. M. Cheng, M. W. Byrom, J. Shelton, and L. P. Ford, “Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis,” Nucleic Acids Research, vol. 33, no. 4, pp. 1290–1297, 2005.
[124]
X. Xiong, H.-Z. Ren, M.-H. Li, J.-H. Mei, J.-F. Wen, and C.-L. Zheng, “Down-regulated miRNA-214 induces a cell cycle G1 arrest in gastric cancer cells by up-regulating the PTEN protein,” Pathology and Oncology Research, vol. 17, no. 4, pp. 931–937, 2011.
[125]
C. Wang, Z. Bian, D. Wei, and J.-G. Zhang, “miR-29b regulates migration of human breast cancer cells,” Molecular and Cellular Biochemistry, vol. 352, no. 1-2, pp. 197–207, 2011.
[126]
C. Zhang, C. Kang, P. Wang et al., “MICRORNA-221 and -222 regulate radiation sensitivity by targeting the PTEN pathway,” International Journal of Radiation Oncology Biology Physics, vol. 80, no. 1, pp. 240–248, 2011.
