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研究生:黃翊棻
研究生(外文):Yi-Fen Huang
論文名稱:探討基底前驅細胞中抑癌基因Pten於攝護腺癌化過程所扮演的角色
論文名稱(外文):The Role of PTEN in the Progression of Prostate Cancer Initiated from Basal Progenitor Cells
指導教授:陳俊銘陳俊銘引用關係
指導教授(外文):Chun-Ming Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生命科學暨基因體科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:66
中文關鍵詞:攝護腺癌抑癌基因Pten癌化過程
外文關鍵詞:PTENprostate cancertumorigenesisbasal cell
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在開發中國家,攝護腺癌為醫學診斷中第二常見的癌症,於男性癌症死亡率則位居第三。攝護腺中至少分為兩種細胞譜系:柱狀上皮細胞和基底幹細胞/前驅細胞,兩者表現不同的角質素標誌,分別為cytokeratin 8 (CK8) 和 cytokeratin 5 (CK5)。目前普遍認為攝護腺癌是由仰賴睪固酮生長的柱狀上皮細胞所增生而來。然而最近許多研究發現,除了柱狀上皮來源,攝護腺癌也可能從具有高度分化能力的幹細胞/前驅細胞所衍生而來。此外在臨床攝護腺癌病例中,經常發現抑癌基因Pten的缺失,導致過度活化PI3K/Akt的訊息傳遞。顯示此具有磷酸酯酶活性的抑癌基因Pten,對於抑制攝護腺癌症發生扮演很重要的角色。若此訊息傳導途徑發生異常,即可能增加罹患攝護腺癌的機率。為了於活體中研究攝護腺癌的癌化過程,探討Pten在單一基底細胞譜系中所執行的功能為何,實驗室利用Tg(BK5-CreERT) 基因轉殖鼠,透過4-OHT的注射可以在基底細胞譜系中,觀察抑癌基因Pten剔除後的表現型。本實驗在BK5-CreERT;Ptenfx/fx誘導式剔除鼠中觀察到攝護腺癌症之發生,並且發現增加基底前驅細胞以及TA細胞群,這些細胞群透過分化成更多的柱狀上皮細胞,進而影響攝護腺癌的癌症潛伏期(latency)。我們發現藉由castration的方式,無法抑制攝護腺癌的生長,推測此小鼠模式可能發展出荷爾蒙抗性攝護腺癌(androgen-independent prostate cancer)。此外我們建立了BK5-CreERT;Ptenfx/fx;Akt1+/-基因剔除鼠,此小鼠於Pten誘導式基因剔除的遺傳背景下再去除一個Akt1對偶基因。在4-OHT注射後九週,我們發現缺少一個Akt1對偶基因可以抑制VP的癌症生長至BPH時期,顯示下游蛋白的表現會影響細胞增生的程度。因此本實驗所建立的Pten誘導式基因剔除小鼠模式,除了能探究攝護腺癌化過程中所參與的機制,並且提供一個發展抑癌藥物治療的動物模式。
Prostate cancer is the second-leading cause of cancer-related deaths among male. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is among the most commonly mutated tumor suppressor gene in human prostate cancer. PTEN inhibits PI3K/Akt-mediated signaling pathway. Deletions or mutations of Pten result in PIP3 accumulation and AKT phosphorylation. PIP3 and pAKT are key signal transducers, which involve in cell proliferation, survival and tumorigenesis. Previously, transgenic mouse strains with prostate specific expression of Cre recombinase such as probasin (PB)-Cre, prostate-specific antigen (PSA)-Cre, and mouse mammary tumor virus (MMTV)-Cre strains have been utilized to ablate Pten gene in the prostate epithelium. These Pten–deficient mouse models result in prostate cancer progression in rodents. To further dissect the different cell types involved in Pten-deficient prostate tumorigenesis, we used the 4-hydroxytamoxifen (4-OHT) induced CreERT to delete loxP-flanked Pten exon 5 (Ptenfx/fx) in basal cells by Bovine Keratin 5 promoter in a temporally controlled manner. The BK5-CreERT mice express CreERT in prostate basal cells, which are thought to have enriched stem/progenitor populations. The cancer progression of BK5-CreERT;Ptenfx/fxmice was benign prostatic hyperplasia (BPH) at 5 weeks and prostatic intraepithelial neoplasia (PIN) as well as prostate cancer at 9 weeks after 4-OHT administration. The increased p-AKT cells were observed in initiation stage (~5 weeks) in this Pten-deficient prostate cancer and decreased during cancer progression. The expression of the cytokeratins as the differentiation markers, cytokeratin 5 (CK5) and CK8, in prostatic epithelial cells was abnormal. Subsequently, I performed IHC using antibodies against Ki67 and BrdU and found the increased proliferative cells in PIN and cancer lesions. By using p63 antibody, I observed an increase p63-positive cells in basal cell compartment. Similarly, the FACS quantification reveals a dramatically increase of progenitor population in Pten-deficient prostate with CD49f and Sca1 antibodies. The result indicates enriched stem/progenitor cells after losing of Pten. Through castration, the mutant prostates could not be suppressed the tumor development. Surprisingly, by a genetic interaction approach: BK5-CreERT;Ptenfx/fx;Akt1+/- mice, we found that the cancer progression was suppressed to the BPH stage in ventral prostate. Taken together, my preliminary findings implicated that this mouse model might provide a mouse model to study the target therapy for androgen-independent prostate cancer and further gain insight into the role of PTEN in the pathogenesis of prostate cancer.
Chinese Abstract ................... 1
English Abstract .................. 2
I. Introduction .................. 4
I-1. The prostatic physiology in mouse and human ................. 4
I-2. Androgen is essential for prostate development ................. 5
I-3. Pten and PI3K/Akt signaling ................. 6
I-4. Physiological role of PTEN in mouse tissues ................. 8
I-5. Pten mutant mouse models in human prostate cancer ................. 9
II. Materials and Methods ................11
II-1. Mice .............11
II-2. Administration of 4-hydroxytamoxifen and BrdU ................12
II-3. Genotyping ................12
II-4. Histology and immunostaining analysis ................13
--- H&E staining ................14
--- Immunohistochemistical staining (IHC) ................14
--- Immunofluorescence staining (IF) ................15
--- Indirect immunofluorescence with tyramide signal amplification ................16
II-5. Fluorescence-activated cell sorting analysis (FACS analysis) ................17
II-6. Statistical analysis ................18
III. Results ................19
III-1. Establishment of basal cell specific PTEN knockout mice ................19
III-2. Loss of Pten causes Prostate cancer in BK5-CreERT; Ptenfx/fx mice ............... 20
III-3. Expression of keratin markers in the prostate epithelium compartment ...……... 20
III-4. The phospho-AKT(S473) expression pattern of Pten-deficient prostate in tumor progression and PI3K/Akt pathway was down-regulated at the PIN and cancer stages ................21 III-5. Increased proliferative cells during cancer progression ................. 23
III-6. Increased p63 in Pten-deficient prostate epithelium ................. 24
III-7. Increased stem/progenitors (Lin-Sca-1+CD49f+) in the Pten ablating prostate ...... 25
III-8. p27Kip protein was decreased in the BK5CreERT-Ptenfx/fx prostate .................. 25
III-9. The prostate cancer proceeded to an androgen-independent tumor type ............. 26
III-10. Genetic interaction of Pten and Akt1 in a temporally controlled tumorigenesis ...............27
IV. Discussion ................... 29
IV-1. Comparison of different mouse models for Pten-deficient CaP progression 29
IV-2. Increased basal progenitor population resulted in quicker tumor progression 29
IV-3. The cancer development might occur through an Akt-independent pathway 30
IV-4. The tumor growth did not suppress following androgen ablation ................... 31
IV-5. Hypothesis for the physiological function of Pten in prostatic basal cells ............ 32
V. References ................... 34
VI. Figures ................... 41
VII. Tables ................... 65
Abate-Shen, C., and Shen, M. M. (2000). Molecular genetics of prostate cancer. Genes Dev 14, 2410-2434.
Abrahamsson, P. A., Cockett, A. T., and di Sant'Agnese, P. A. (1998). Prognostic significance of neuroendocrine differentiation in clinically localized prostatic carcinoma. Prostate Suppl 8, 37-42.
Ali, I. U., Schriml, L. M., and Dean, M. (1999). Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 91, 1922-1932.
Backman, S. A., Ghazarian, D., So, K., Sanchez, O., Wagner, K. U., Hennighausen, L., Suzuki, A., Tsao, M. S., Chapman, W. B., Stambolic, V., and Mak, T. W. (2004). Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten. Proc Natl Acad Sci U S A 101, 1725-1730.
Backman, S. A., Stambolic, V., Suzuki, A., Haight, J., Elia, A., Pretorius, J., Tsao, M. S., Shannon, P., Bolon, B., Ivy, G. O., and Mak, T. W. (2001). Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 29, 396-403.
Bose, S., Crane, A., Hibshoosh, H., Mansukhani, M., Sandweis, L., and Parsons, R. (2002). Reduced expression of PTEN correlates with breast cancer progression. Hum Pathol 33, 405-409.
Brawer, M. K., Peehl, D. M., Stamey, T. A., and Bostwick, D. G. (1985). Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res 45, 3663-3667.
Bui, M., and Reiter, R. E. (1998). Stem cell genes in androgen-independent prostate cancer. Cancer Metastasis Rev 17, 391-399.
Chen, M. L., Xu, P. Z., Peng, X. D., Chen, W. S., Guzman, G., Yang, X., Di Cristofano, A., Pandolfi, P. P., and Hay, N. (2006). The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes Dev 20, 1569-1574.
Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F., and Birnbaum, M. J. (2001). Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276, 38349-38352.
Chu, E. C., and Tarnawski, A. S. (2004). PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit 10, RA235-241.
Chu, I. M., Hengst, L., and Slingerland, J. M. (2008). The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8, 253-267.
Crackower, M. A., Oudit, G. Y., Kozieradzki, I., Sarao, R., Sun, H., Sasaki, T., Hirsch, E., Suzuki, A., Shioi, T., Irie-Sasaki, J., et al. (2002). Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737-749.
Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M., and Hemmings, B. A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789.
Cunha, G. R., Cooke, P. S., and Kurita, T. (2004). Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol 67, 417-434.
Datta, S. R., Brunet, A., and Greenberg, M. E. (1999). Cellular survival: a play in three Akts. Genes Dev 13, 2905-2927.
De Marzo, A. M., Nelson, W. G., Meeker, A. K., and Coffey, D. S. (1998). Stem cell features of benign and malignant prostate epithelial cells. J Urol 160, 2381-2392.
Denis, L., Dalesio, O., and Murphy, G. (1993). [Review of phase III clinical trials on combined anti-androgen therapies in patients with metastasized prostatic cancer]. Prog Urol 3, 75-85.
Deocampo, N. D., Huang, H., and Tindall, D. J. (2003). The role of PTEN in the progression and survival of prostate cancer. Minerva Endocrinol 28, 145-153.
Di Cristofano, A., and Pandolfi, P. P. (2000). The multiple roles of PTEN in tumor suppression. Cell 100, 387-390.
Di Cristofano, A., Pesce, B., Cordon-Cardo, C., and Pandolfi, P. P. (1998). Pten is essential for embryonic development and tumour suppression. Nat Genet 19, 348-355.
di Sant'Agnese, P. A. (1992). Neuroendocrine differentiation in human prostatic carcinoma. Hum Pathol 23, 287-296.
Fuller, P. J. (1991). The steroid receptor superfamily: mechanisms of diversity. FASEB J 5, 3092-3099.
Gao, J., Arnold, J. T., and Isaacs, J. T. (2001). Conversion from a paracrine to an autocrine mechanism of androgen-stimulated growth during malignant transformation of prostatic epithelial cells. Cancer Res 61, 5038-5044.
Goldstein, A. S., Lawson, D. A., Cheng, D., Sun, W., Garraway, I. P., and Witte, O. N. (2008). Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc Natl Acad Sci U S A 105, 20882-20887.
Groszer, M., Erickson, R., Scripture-Adams, D. D., Dougherty, J. D., Le Belle, J., Zack, J. A., Geschwind, D. H., Liu, X., Kornblum, H. I., and Wu, H. (2006). PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci U S A 103, 111-116.
Hayashi, N., Sugimura, Y., Kawamura, J., Donjacour, A. A., and Cunha, G. R. (1991). Morphological and functional heterogeneity in the rat prostatic gland. Biol Reprod 45, 308-321.
He, X. C., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., Dirisina, R., Porter-Westpfahl, K. S., Hembree, M., Johnson, T., et al. (2007). PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet 39, 189-198.
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., and Thun, M. J. (2009). Cancer statistics, 2009. CA Cancer J Clin.
Koster, M. I., Kim, S., Mills, A. A., DeMayo, F. J., and Roop, D. R. (2004). p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 18, 126-131.
Kurita, T., and Cunha, G. R. (2001). Roles of p63 in differentiation of Mullerian duct epithelial cells. Ann N Y Acad Sci 948, 9-12.
Kwon, C. H., Zhu, X., Zhang, J., Knoop, L. L., Tharp, R., Smeyne, R. J., Eberhart, C. G., Burger, P. C., and Baker, S. J. (2001). Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet 29, 404-411.
Kyprianou, N., English, H. F., and Isaacs, J. T. (1990). Programmed cell death during regression of PC-82 human prostate cancer following androgen ablation. Cancer Res 50, 3748-3753.
Lawson, D. A., Xin, L., Lukacs, R. U., Cheng, D., and Witte, O. N. (2007). Isolation and functional characterization of murine prostate stem cells. Proc Natl Acad Sci U S A 104, 181-186.
Lee, J. O., Yang, H., Georgescu, M. M., Di Cristofano, A., Maehama, T., Shi, Y., Dixon, J. E., Pandolfi, P., and Pavletich, N. P. (1999). Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99, 323-334.
Lehrer, M. S., Sun, T. T., and Lavker, R. M. (1998). Strategies of epithelial repair: modulation of stem cell and transit amplifying cell proliferation. J Cell Sci 111 ( Pt 19), 2867-2875.
Lesche, R., Groszer, M., Gao, J., Wang, Y., Messing, A., Sun, H., Liu, X., and Wu, H. (2002). Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 32, 148-149.
Li, D. M., and Sun, H. (1997). TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57, 2124-2129.
Li, G., Robinson, G. W., Lesche, R., Martinez-Diaz, H., Jiang, Z., Rozengurt, N., Wagner, K. U., Wu, D. C., Lane, T. F., Liu, X., et al. (2002). Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development 129, 4159-4170.
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943-1947.
Liang, C. C., You, L. R., Chang, J. L., Tsai, T. F., and Chen, C. M. (2009). Transgenic mice exhibiting inducible and spontaneous Cre activities driven by a bovine keratin 5 promoter that can be used for the conditional analysis of basal epithelial cells in multiple organs. J Biomed Sci 16, 2.
Litvinov, I. V., De Marzo, A. M., and Isaacs, J. T. (2003). Is the Achilles' heel for prostate cancer therapy a gain of function in androgen receptor signaling? J Clin Endocrinol Metab 88, 2972-2982.
Liu, A. Y., True, L. D., LaTray, L., Nelson, P. S., Ellis, W. J., Vessella, R. L., Lange, P. H., Hood, L., and van den Engh, G. (1997). Cell-cell interaction in prostate gene regulation and cytodifferentiation. Proc Natl Acad Sci U S A 94, 10705-10710.
Loda, M., Cukor, B., Tam, S. W., Lavin, P., Fiorentino, M., Draetta, G. F., Jessup, J. M., and Pagano, M. (1997). Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med 3, 231-234.
Lu, T. L., Chang, J. L., Liang, C. C., You, L. R., and Chen, C. M. (2007). Tumor spectrum, tumor latency and tumor incidence of the Pten-deficient mice. PLoS ONE 2, e1237.
Ma, X., Ziel-van der Made, A. C., Autar, B., van der Korput, H. A., Vermeij, M., van Duijn, P., Cleutjens, K. B., de Krijger, R., Krimpenfort, P., Berns, A., et al. (2005). Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis. Cancer Res 65, 5730-5739.
Maehama, T., and Dixon, J. E. (1998). The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273, 13375-13378.
Mayo, L. D., and Donner, D. B. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 98, 11598-11603.
McNeal, J. E. (1969). Origin and development of carcinoma in the prostate. Cancer 23, 24-34.
McNeal, J. E. (1988). Normal histology of the prostate. Am J Surg Pathol 12, 619-633.
Myers, M. P., Pass, I., Batty, I. H., Van der Kaay, J., Stolarov, J. P., Hemmings, B. A., Wigler, M. H., Downes, C. P., and Tonks, N. K. (1998). The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 95, 13513-13518.
Nagle, R. B., Ahmann, F. R., McDaniel, K. M., Paquin, M. L., Clark, V. A., and Celniker, A. (1987). Cytokeratin characterization of human prostatic carcinoma and its derived cell lines. Cancer Res 47, 281-286.
Podsypanina, K., Ellenson, L. H., Nemes, A., Gu, J., Tamura, M., Yamada, K. M., Cordon-Cardo, C., Catoretti, G., Fisher, P. E., and Parsons, R. (1999). Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 96, 1563-1568.
Porter, P. L., Malone, K. E., Heagerty, P. J., Alexander, G. M., Gatti, L. A., Firpo, E. J., Daling, J. R., and Roberts, J. M. (1997). Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3, 222-225.
Potten, C. S., and Loeffler, M. (1990). Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001-1020.
Rasheed, B. K., Stenzel, T. T., McLendon, R. E., Parsons, R., Friedman, A. H., Friedman, H. S., Bigner, D. D., and Bigner, S. H. (1997). PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 57, 4187-4190.
Romashkova, J. A., and Makarov, S. S. (1999). NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401, 86-90.
Signoretti, S., Waltregny, D., Dilks, J., Isaac, B., Lin, D., Garraway, L., Yang, A., Montironi, R., McKeon, F., and Loda, M. (2000). p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 157, 1769-1775.
Slingerland, J., and Pagano, M. (2000). Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 183, 10-17.
Stambolic, V., Suzuki, A., de la Pompa, J. L., Brothers, G. M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J. M., Siderovski, D. P., and Mak, T. W. (1998). Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29-39.
Steck, P. A., Pershouse, M. A., Jasser, S. A., Yung, W. K., Lin, H., Ligon, A. H., Langford, L. A., Baumgard, M. L., Hattier, T., Davis, T., et al. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15, 356-362.
Stiles, B., Groszer, M., Wang, S., Jiao, J., and Wu, H. (2004). PTENless means more. Dev Biol 273, 175-184.
Sugimura, Y., Cunha, G. R., and Donjacour, A. A. (1986). Morphogenesis of ductal networks in the mouse prostate. Biol Reprod 34, 961-971.
Sun, H., Enomoto, T., Shroyer, K. R., Ozaki, K., Fujita, M., Ueda, Y., Nakashima, R., Kuragaki, C., Ueda, G., and Murata, Y. (2002). Clonal analysis and mutations in the PTEN and the K-ras genes in endometrial hyperplasia. Diagn Mol Pathol 11, 204-211.
Suzuki, A., de la Pompa, J. L., Stambolic, V., Elia, A. J., Sasaki, T., del Barco Barrantes, I., Ho, A., Wakeham, A., Itie, A., Khoo, W., et al. (1998). High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8, 1169-1178.
Suzuki, A., Itami, S., Ohishi, M., Hamada, K., Inoue, T., Komazawa, N., Senoo, H., Sasaki, T., Takeda, J., Manabe, M., et al. (2003). Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation. Cancer Res 63, 674-681.
Suzuki, A., Yamaguchi, M. T., Ohteki, T., Sasaki, T., Kaisho, T., Kimura, Y., Yoshida, R., Wakeham, A., Higuchi, T., Fukumoto, M., et al. (2001). T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523-534.
Taesch, S., and Niese, D. (1994). Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients. Transpl Int 7 Suppl 1, S263-266.
Uzgare, A. R., and Isaacs, J. T. (2004). Enhanced redundancy in Akt and mitogen-activated protein kinase-induced survival of malignant versus normal prostate epithelial cells. Cancer Res 64, 6190-6199.
Verhagen, A. P., Aalders, T. W., Ramaekers, F. C., Debruyne, F. M., and Schalken, J. A. (1988). Differential expression of keratins in the basal and luminal compartments of rat prostatic epithelium during degeneration and regeneration. Prostate 13, 25-38.
Wang, S., Gao, J., Lei, Q., Rozengurt, N., Pritchard, C., Jiao, J., Thomas, G. V., Li, G., Roy-Burman, P., Nelson, P. S., et al. (2003). Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209-221.
Wu, X., Hepner, K., Castelino-Prabhu, S., Do, D., Kaye, M. B., Yuan, X. J., Wood, J., Ross, C., Sawyers, C. L., and Whang, Y. E. (2000a). Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci U S A 97, 4233-4238.
Wu, X., Wu, J., Huang, J., Powell, W. C., Zhang, J., Matusik, R. J., Sangiorgi, F. O., Maxson, R. E., Sucov, H. M., and Roy-Burman, P. (2001). Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev 101, 61-69.
Wu, Y., Dowbenko, D., Spencer, S., Laura, R., Lee, J., Gu, Q., and Lasky, L. A. (2000b). Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem 275, 21477-21485.
Xin, L., Lawson, D. A., and Witte, O. N. (2005). The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 102, 6942-6947.
Xin, L., Lukacs, R. U., Lawson, D. A., Cheng, D., and Witte, O. N. (2007). Self-renewal and multilineage differentiation in vitro from murine prostate stem cells. Stem Cells 25, 2760-2769.
Yilmaz, O. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., and Morrison, S. J. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475-482.
Zenzmaier, C., Untergasser, G., and Berger, P. (2008). Aging of the prostate epithelial stem/progenitor cell. Exp Gerontol 43, 981-985.
Zhou, X. P., Loukola, A., Salovaara, R., Nystrom-Lahti, M., Peltomaki, P., de la Chapelle, A., Aaltonen, L. A., and Eng, C. (2002). PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol 161, 439-447.
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