中文摘要
磷酸酶Protein phosphatase 2A， 以下簡稱PP2A，屬於一種serine / threonine的磷酸酶。參與很多細胞內的調節作用，例如:參與細胞內的訊息傳遞、調節細胞週期的進行、及調控細胞的生長及細胞凋亡等等。而PP2A主要是由一個36-kDa的催化次單元，稱之為C次單元；及一個65-kDa的結構次單元，稱之為A次單元；以及具有調節功能的B次單元所組成的三元複合體。目前相信B次單元能夠決定PP2A的受質特異性 ，此外B次單元又區分為B(B55/PR55)、B’ (B56/PR61)、B” (PR72/PR130) 以及 B”’(striatin/ SG2NA) 四個不同的家族。而在B’家族中又包含 、、、以及五種不同的異構型。B563則屬於B’家族中的一個spliced variants。此外最近的研究證據指出：在一些人類的肺癌細胞中，會失去PP2A/ B56的表現；同時又發現將PP2A/ B563送入細胞過度表現時，能夠減低這些癌細胞的癌化特性。因此這些證據暗示著： B56次單元也許扮演一個調節細胞轉型的角色，而這個次單元的表現的變異也許會影響腫瘤的形成。因此我的研究方向，主要想探討B56次單元在細胞中所扮演的調節功能為何，是否與PP2A扮演腫瘤抑制的角色有關呢？在NIH 3T3細胞及COS-7細胞中，利用轉染法結合免疫螢光染色的技術及GFP-tagging的方法去評估B56次單元在細胞中的表現位置。我們發現B56次單元主要集中在細胞核表現 ，更有趣的是：一些過度表現B56次單元的細胞會有不正常的細胞型態，類似凋亡的細胞，並且有細胞核皺縮的情形。但是更有趣的是，我們發現在篩選的穩定表現B56次單元的NIH 3T3細胞群，除了有些仍保持集中在核的表現外，大部分是呈現細胞核及細胞質均質表現，有少數甚至是在細胞質中有較多的表現。此外也發現過度表現B56次單元的細胞，相較於pMSCV vector alone表現的細胞，會延遲NIH 3T3細胞的細胞生長。在進一步分析細胞週期分布的情形 ，發現到過度表現B56次單元的細胞其G1、G2/M phase 會減少而S phase會增加，因此我們初步推測B56次單元的大量表現可能會導致細胞週期的S-phase停滯。另一方面，當給予細胞serum withdrawl的刺激時 ，也發現過度表現的B56次單元會增加細胞死亡現象。此外對於訊息傳遞的影響，則觀察到B56次單元能夠明顯的降低激酶AKT在Threonine 308位點的磷酸化；但是對於Serine 473位點則沒有影響；另外對於extracellular signal –regulated kinases (Erk1/2) 並沒有顯著的影響。所以綜合上述的研究結果 ，我們發現B56次單元的表現位置是可具變動性，而且可能與其調節的功能有關，當其過度表現時，延遲了細胞的生長，其可能的機制是透過調控S-phase停滯或是促成細胞凋亡所造成。

Abstract
Protein phosphatase 2A (PP2A) belongs to a family of serine/threonine phosphates, and is involved in a regulation of broad range of cellular processes, such as signal transduction, cell cycle regulation, cell growth and cell death. The holoenzyme of PP2A consists of a 36-kDa catalytic C subunit, a 65-kDa structural A subunit, and a variable regulatory B subunit, which is thought to determine the substrate specificity and subcellular localization of PP2A. At present, four different families of B subunit have been identified, termed B (B55/PR55), B’(B56/PR61) , B” (PR72/PR130, PR59, PR48), and B”’(striatin, SG2NA). Among these, the B’family contains at least five distinct gene products, denoted , ,and and B563 belongs to one of the spliced variants of B’family. Recent evidence has shown that loss of expression of PP2A B56 in some human lung cancer cell lines, whereas expression of PP2A B56reversed the tumorigencity of these cells. These findings suggest that PP2AB563 may play a tumor suppressor role, and alterations in expression of this subunit may contribute to cancer development. We aim to investigate the regulatory function of B563 subunit which may be involved in tumor suppressor function of PP2A. At present, we report that HA-tagged B563 is predominantly nuclear localized by GFP-tagging and immunofluorescence staining in both NIH 3T3 and COS-7 cells by transient transfection experiments. In addition, forced overexpression of B563 resulted in nuclear condensation in some transfected cells, and, to some extent, caused abnormal nuclear and cell morphology similar to apoptotic cells. Interestingly, in a NIH3T3 pool stably expressing B563, expression of B563 became evenly distributed throughout the cell in most of the cells. Moreover, overexpression of B563 retarded growth of NIH 3T3 cells, modestly decreased cells in G1, G2/M phase but increased in S phase of cell cycle. Besides, overexpression of B563 caused a significant increase in cell death of NIH 3T3 cells after serum withdrawl as compared to cells expressing vector alone. We also investigated whether B563 overexpression affected main signaling pathways regulating cell survival and proliferation in NIH 3T3 cells. And we found that overexpression of B563 resulted in significant decrease in phosphorylation of AKT at threonine 308 site and almost no changes of phosphorylation at serine473 site as compared to that of expressing vector-alone cells by serum stimulation . In addition, overexpression of B563 had little effect on phosphorylation of extracellular signal regulated kinases (Erks). In summary, our findings suggest that a role of PP2A B563 subunit in regulating cell cycle progression and apoptosis. In addition, B563 was predominantly localized to the nuclei in transiently transfected cells, while the expression of the protein became evenly distributed throughout the cells after stable expression. These results implicate that the subcellular localization of B563 may determine its regulatory function in cells.

參考文獻

1. Arino, J., Woon, C. W., Brautigan, D. L. and Miller Jr, T. B. Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc. Natl. Acad. Sci. U.S.A. 85, 4252-4256, (1988).
2. Bialojan, C. and Takai, A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Biochem. J. 256, 283-290, (1988).
3. Bartek, J.; Bartkova, J.; Lukas, J. The retinoblastoma protein pathway in cell cycle control and cancer. Exp. Cell Res. 237:1- 6, (1997).
4. Baysal, B. E., Farr, J. E., Goss, J. R., Devlin, B. and Richard, III, C. W. : Genomic organization and precise physical location of protein phosphatase 2A regulatory subunit A beta isoform gene on chromosome band 11q23. Gene 217, 107-116, (1998).
5. Bennin DA, Arachchige Don AS, Brake T, McKenzie JL, Rosenbaum H, Ortiz L, DePaoli-Roach AA, Horne MC: Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B( subunits in active complexes and induces nuclear aberrations and G1/S phase cell cycle arrest. J Biol Chem, 277:27449-27467, (2002).
6. Cowley, S., Paterson, H., Kemp, P. & Marshall, C.J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841-852, (1994).
7. Csortos, C., Zolnierowicz, S., Bako, E., Durbin, S. D. and DePaoli-Roach, A. A. High complexity in the expression of the B’ subunit of protein phosphatase 2A0. Evidence for the existence of at least seven novel isoforms. J. Biol. Chem. 271, 2578-2588, (1996).
8. Chen, J., Peterson, R.T. & Schreiber, S.L. Alpha 4 associates with protein phosphatases 2A, 4 and 6. Biochem. Biophys. Res. Commun. 247, 827-832, (1998).
9. Cohen PT et al. Novel protein serine /threonine phosphatases:
variety is the specific life. Trands Biochem Sci, 22:245-51, (1997).
10. Chew, Y. P.; Ellis, M.; Wilkie, S.; Mittnacht, S. pRB phosphorylation
mutants reveal role of pRB in regulating S phase completion by a
mechanism independent of E2F. Oncogene, 17:2177-2186, (1998).
11. Calin, G. A., de Iasio, M. G., Caprini, E., Vorechovsky, I., Natali, P. G., Sozzi, G., Croce, C. M., Barbanti-Brodano, G., Russo, G. and Negrini, M. Low frequency of alterations of the  (PPP2R1A) and (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene 19, 1191-1195, (2000).
12. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC,
Hahn WC: Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell, 5:127-136, (2004).
13. Deng, X., Ito, T., Carr, B., Mumby, M. and May Jr, S. Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J. Biol. Chem. 273, 34157-34163, (1998).
14. Estelle Sontag. Protein phosphatase 2A: the Trojan Horse of
cellular signaling. Cellular Signalling 13:7-16, (2001).
15. Evans, D.R. & Simon, J.A. The predicted beta12-beta13 loop is important for inhibition of PP2Ac alpha by the antitumor drug fostriecin. FEBS Lett. 498, 110-115, (2001).
16. Francia, G., Poulsom, R., Hanby, A. M., Mitchell, S. D., Williams, G., McKee, P. and Hart, I. R. Identification by differential display of a protein phosphatase-2A regulatory subunit preferentially expressed in malignant melanoma cells. Int. J. Cancer 82, 709-713, (1999).
17. Green, D. D., Yang, S.-I. and Mumby, M. C. Molecular cloning and sequence analysis of the catalytic subunit of bovine type 2A protein phosphatase. Proc. Natl. Acad. Sci. U.S.A. 84, 4880-4884, (1987).
18. Gomez, N. & Cohen, P. Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases. Nature 353, 170-173, (1991).
19. Graeber, T.G., Peterson, J.F., Tsai, M., Monica, K., Fornace, A., J., Jr. & Giaccia, A., J. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol. Cell. Biol. 14, 6264-6277, (1994).
20. Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D:
The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell, 96:99-110, (1999).
21. Hemmings, B. A., Adams-Pearson, C., Maurer, F., Mu$ ller, P., Goris, J., Merlevede, W., Hofsteenge, J. and Stone, S. R. - and -forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 29, 3166-3173, (1990).
22. Healy, A. M., Zolnierowicz, S., Stapleton, A. E., Goebl, M., DePaoli-Roach, A. A. and Pringle, J. R. CDC55, a Saccharomyces cerevisiae gene involved in cellular morphogenesis : identification, characterization, and homology to the B subunit of mammalian type 2A protein phosphatase. Mol. Cell. Biol. 11, 5767-5780, (1991).
23. Hendrix, P., Mayer-Jaekel, R. E., Cron, P., Goris, J., Hofsteenge, J., Merlevede, W. and Hemmings, B. A. Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing. J. Biol. Chem. 268, 15267-15276, (1993).
24. Ito A, Kataoka TR, Watanabe M, Nishiyama K, Mazaki Y, Sabe H, Kitamara Y, Nojima H: A truncated isoform of the PP2A B56 subunit promotes cell motility through paxillin phosphorylation. EMBO J, 19:562-571, (2000).
25. Ito A, Koma Y, Watabe K, Nagano T, Endo Y, Nojima H, Kitamara Y: A truncated isoform of the protein phosphatase 2A B56 regulatory subunit may promote genetic instability and cause tumor progression. Am J Pathol, 162:81-91, (2003).
26. Ito A, Koma Y, Sohda M, Watabe K, Nagano T, Misumi Y, Endo Y,
Nojima H, Kitamara Y: Localization of the PP2A B56 regulatory subunit at the Golgi complex. Am J Pathol, 162:479-489, (2003).
27. Jones, T. A., Barker, H. M., Da Cruz e Silva, E. F., Mayer-Jaekel, R. E., Hemmings, B. A., Spurr, N. K., Sheer, D. and Cohen, P. T. W. Localization of the genes encoding the catalytic subunits of protein phosphatase 2A to human chromosome bands 5q23-q31 and 8p12-p11.2, respectively. Cytogenet. Cell Genet. 63, 35-41, (1993).
28. Jaso D Arroyo, William C Hahn: Involvement of PP2A in viral and cellular transformation. Oncogene, 24:7746-7755, (2005).
29. Khew-Goodall, Y., Mayer, R. E., Maurer, F., Stone, S. R. and Hemmings, B. A. Structure and transcriptional regulation of protein phosphatase 2A catalytic subunit genes. Biochemistry 30, 89-97, (1991).
30. Kleinberger, T. and Shenk, T. Adenovirus E4orf4 protein binds to protein phosphatase 2A, and the complex down regulates E1A-enhanced junB transcription. J. Virol. 67, 7556-7560, (1993).
31. Kremmer, E., Ohst, K., Kiefer, J., Brewis, N. and Walter, G.
Separation of PP2A core enzyme and holoenzyme with monoclonal
antibodies against the regulatory A subunit : abundant expression of
both forms in cells. Mol. Cell. Biol. 17,1692-1701, (1997).
32. Kawada, M., Amemiya, M., Ishizuka, M. and Takeuchi, T. Cytostatin, an inhibitor of cell adhesion to extracellular matrix, selectively inhibits protein phosphatase 2A. Biochim. Biophys. Acta 1452, 209-217, (1999).
33. Karaisoku, A., Jessus, C., Brassac, T. & Ozon, R. Phosphatase 2A and polo kinase, two antagonistic regulators of cdc25 activation and MPF auto-amplification. J. Cell Sci. 112, 3747-3756, (1999).
34. Knudsen, K. E.; Booth, D.; Naderi, S.; Sever-Chroneos, Z.; Fribourg, A. F.; Hunton, I. C.; Feramisco, J. R.; Wang, J. Y.; Knudsen, E. S.
RB-dependent S-phase response to DNA damage. Mol. Cell. Biol. 20 : 7751-7763, (2000).
35. Kimura SH, Nojima H: Cyclin G1 associates with MDM2 and regulates accumulation and degradation of p53 protein. Genes Cells, 7:869-880, (2002).
36. Koma YI, Ito A, Watabe K, Kimura SH, Kitamura Y: A truncated isoform of the PP2A B56 gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance. Histol Histopathol, 19:391-400, (2004).
37. Li, H., Zhao, L.-L., Funder, J. W. and Liu, J.-P. Protein phosphatase 2A inhibits nuclear telomerase activity in human breast cancer cells. J. Biol. Chem. 272, 16729-16732, (1997).
38. Li, X., Yost, H.J., Virshup, D.M. & Seeling, J.M. Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus. EMBO J. 20, 4122-4131, (2001).
39. Mayer, R. E., Hendrix, P., Cron, P., Matthies, R., Stone, S. R., Goris, J., Merlevede, W., Hofsteenge, J. and Hemmings, B. A. Structure of the 55-kDa regulatory subunit of protein phosphatase 2A: evidence for a neuronal-specific isoform. Biochemistry 30, 3589-3596, (1991).
40. Mayer-Jaekel, R.E., Ohkura, H., Gomes, R., Sunkel, C.E., Baumgartner, S., Hemmings, B.A. & Glover, D.M. The 55 kd regulatory subunit of Drosophila protein phosphatase 2A is required for anaphase. Cell 72, 621-633, (1993).
41. McCright, B. and Virshup, D. M. Identification of a new family of protein phosphatase 2A regulatory subunits. J. Biol. Chem. 270, 26123-26128, (1995).
42. McCright, B., Rivers, A. M., Audlin, S. and Virshup, D. M. The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. J. Biol. Chem. 271, 22081-22089, (1996).
43. McCright, B., Brothman, A. R. and Virshup, D. M. Assignment of human protein phosphatase 2A regulatory subunit genes B56, B56, B56, B56, and B56 (PPP2R5A-PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2!p12. Genomics 36, 168-170, (1996).
44. Murata, K., Wu, J. & Brautigan, D.L. B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc. Natl. Acad. Sci. U.S.A. 94, 10624-1069, (1997).
45. Millward, T.A., Zolnierowicz, S. & Hemmings, B.A. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem. Sci. 24, 186-191, (1999).
46. Moreno, C. S., Park, S., Nelson, K., Ashby, D., Hubalek, F., Lane, W. S. and Pallas, D. C. WD40 repeat proteins striatin and S/G2 nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. J. Biol. Chem. 275, 5257-5263, (2000).
47. Marcellus, R. C., Chan, H., Paquette, D., Thirlwell, S., Boivin, D. and Branton, P. E. Induction of p53-independent apoptosis by the adenovirus E4orf4 protein requires binding to the B subunit of protein phosphatase 2A. J. Virol. 74, 7869-7877, (2000).
48. Nakamura, K.; Koda, T.; Kakinuma, M.; Matsuzawa, S.; Kitamura, K.; Mizuno, Y.; Kikuchi, K. Cell cycle dependent gene expressions and activities of protein phosphatases PP1 and PP2A in mouse NIH3T3 fibroblasts. Biochem. Biophys. Res. Commun. 187:507-514, (1992).
49. Nagase, T., Murakami, T., Nozaki, H., Inoue, R., Nishito, Y., Tanabe, O., Usui, H. and Takeda, M. Tissue and subcellular distributions, and characterization of rat brain protein phosphatase 2A containing a 72-kDa /B” subunit. J. Biochem. (Tokyo) 122, 178-187, (1997).
50. Nigg, E.A. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol. 2, 21-32, (2001).
51. Okamoto, K., Kamibayashi, C., Serrano, M., Prives, C., Mumby, M.C. & Beach, D. p53-dependent association between cyclin G and the B’ subunit of protein phosphatase 2A. Mol. Cell. Biol. 16, 6593-6602, (1996).
52. Orth, K., O`Rourke, K., Salvesen, G.S. & Dixit, V.M. Molecular ordering of apoptotic mammalian CED-3/ICE-like proteases. J. Biol. Chem. 271, 20977-20980, (1996).
53. Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS,
Prives C: Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell, 9:761-771, (2002).
54. Pallas DC, Shahrik LK, Martin BL, Jaspers TB, Miller TB, Brautigan DL, Roberts TM: Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Cell, 60:167-176, (1990).
55. Priya Ranjan, Nicholas H. Heintz *: S-phase arrest by reactive nitrogen species is bypassed by okadaic acid, an inhibitor of protein phosphatases PP1/PP2A. Free Radical Biology & Medicine 40, 247 -259, (2006).
56. Ruediger, R., Roeckel, D., Fait, J., Bergqvist, A., Magnusson, G. and Walter, G. Identification of binding sites on the regulatory A subunit of protein phosphatase 2A for the catalytic C subunit and for tumor antigens of Simian Virus 40 and polyomavirus. Mol. Cell. Biol. 12, 4872-4882, (1992).
57. Ruediger, R., Hentz, M., Fait, J., Mumby, M. and Walter, G. Molecular model of the A subunit of protein phosphatase 2A: interaction with other subunits and tumor antigens. J. Virol. 68, 123-129, (1994).
58. Ruvolo, P. P., Deng, X., Ito, T., Carr, B. K. and May, W. S. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J. Biol. Chem. 274, 20296-20300, (1999).
59. Stone, S. R., Hofsteenge, J. and Hemmings, B. A. Molecular cloning of cDNAs encoding two isoforms of the catalytic subunit of protein phosphatase 2A. Biochemistry 26, 7215-7220, (1987).
60. Suganuma, M., Fujiki, H., Suguri, H., Yoshizawa, S., Hirota, M., Nakayasu, M., Ojika, M., Wakamatsu, K., Yamada, K. and Sugimura, T. Okadaic acid : an additional non-phorbol-12 –tetradecanoate -13-acetate-type tumor promoter. Proc. Natl. Acad. Sci. U.S.A. 85, 1768-1771, (1988).
61. Sontag, E., Fedorov, S., Kamibayashi, C., Robbins, D., Cobb, M. & Mumby, M.C. The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the MAP kinase pathway and induces cell proliferation. Cell 75, 887-897, (1993).
62. Strack, S., Zaucha, J. A., Ebner, F. F., Colbran, R. J. and Wadzinski, B. E. Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits. J. Comp. Neurol. 392, 515-527, (1998).
63. Santoro, M.F., Annard, R.R., Robertson, M.M., Peng, Y.W., Brady, M.J., Mankovich, J.A., Hacket, M.C., Ghayur, T., Walter, G., Wong, G.G. & Giegel, D.A. Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis. J. Biol. Chem. 273, 13119-13128, (1998).
64. Strack, S., Chang, D., Zaucha, J. A., Colbran, R. J. and Wadzinski, B. E. Cloning and characterization of B delta, a novel regulatory subunit of protein phosphatase 2A. FEBS Lett. 460, 462-466, (1999).
65. Seeling, J.M., Miller, J.R, Gil, R., Moon, R.T., White, R. & Virshup, D.M. Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. Science 283, 2089-2091, (1999).
66. Shtrichman, R., Sharf, R., Barr, H., Dobner, T. and Kleinberger, T. Induction of apoptosis by adenovirus E4orf4 protein is speci®c to transformed cells and requires an interaction with protein phosphatase 2A. Proc. Natl. Acad. Sci. U.S.A. 96, 10080-10085, (1999).
67. Shtrichman, R., Sharf, R. and Kleinberger, T. Adenovirus E4orf4 protein interacts with both B and B subunits of protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by the interaction with Ba. Oncogene 19, 3757-3765, (2000).
68. Sever-Chroneos, Z.; Angus, S. P.; Fribourg, A. F.; Wan, H.; Todorov, I.; Knudsen, K. E.; Knudsen, E. S. Retinoblastoma tumor suppressor protein signals through inhibition of cyclin-dependent kinase 2 activity to disrupt PCNA function in S phase. Mol. Cell. Biol. 21:4032-4045, (2001).
69. Tehrani, M. A., Mumby, M. C. and Kamibayashi, C. Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle. J. Biol. Chem. 271, 5164-5170, (1996).
70. Tanabe, O., Nagase, T., Murakami, T., Nozaki, H., Usui, H., Nishito, Y., Hayashi, H., Kagamiyama, H. and Takeda, M. Molecular cloning of a 74-kDa regulatory subunit (B” or ) of human protein phosphatase 2A. FEBS Lett. 379, 107-111, (1996).
71. Turowski, P., Myles, T., Hemmings, B.A., Fernandez, A. & Lamb, N.J. Vimentin dephosphorylation by protein phosphatase 2A is modulated by the targeting subunit B55. Mol. Biol. Cell 10, 1997-2015, (1999).
72. Voorhoeve, P. M., Hijmans, E. M. and Bernards, R. Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein. Oncogene 18, 515-524, (1999).
73. Wera S, Fernandez A, Lamb NJ, Turowski P, Hemmings- Mieszczak M, Mayer-Jaekel RE, Hemmings BA: Deregulation of translational control of the 65-kDa regulatory subunit (PR65 alpha) of protein phosphatase 2A leads to multinucleated cells. J Biol Chem, 270:21374-21381, (1995).
74. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81: 323 -330, (1995).
75. Wang, S. S., Esplin, E. D., Li, J. L., Huang, L., Gazdar, A., Minna, J. and Evans, G. A. Alterations of the PPP2R1B gene in human lung and colon cancer. Science 282, 284-287, (1998).
76. Yan, Y.; Mumby, M. C. Distinct roles for PP1 and PP2A in phosphorylation of the retinoblastoma protein: PP2A regulates the activities of G1 cyclin-dependent kinases. J. Biol. Chem. 274: 31917-31924, (1999).
77. Yan, Z., Federov, S. A., Mumby, M. C. and Williams, R. S. PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells. Mol. Cell. Biol. 20, 1021-1029, (2000).
78. Zolnierowicz, S., Csortos, C., Bondor, J., Verin, A., Mumby, M. C. and DePaoli-Roach, A. A. Diversity in the regulatory B-subunits of protein phosphatase 2A: identification of a novel isoform highly expressed in brain. Biochemistry 33, 11858-11867, (1994).
79. Zolnierowicz, S., Van Hoof, C., Andjelkovic, N., Cron, P., Stevens, I., Merlevede, W., Goris, J. and Hemmings, B. A. The variable subunit associated with protein phosphatase 2A0 defines a novel multimember family of regulatory subunits. Biochem. J. 317, 187-194, (1996).
80. Zhanyun Tang, Hongjun Shu, Wei Qi, Nadir Mahmood, Marc C. Mumby, and Hongtao Yu*: PP2A Is Required for Centromeric Localization of Sgo1 and Proper Chromosome Segregation. Developmental Cell 10, 1-11, May, (2000).
81. Qing Lu*, David C. Pallas†‡, Howard K. Surks*, Wendy E. Baur*, Michael E. Mendelsohn*, and Richard H. Karas*: Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor. PNAS, vol.101: 17126-17131, December 7, (2004).
82. Svante Resjo et al., Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocyte. Cellular Signalling, 14:231-238, (2002).
83. Steven C. Sansom‡, James D. Stockand§, David Hall, and Bruce Williams: Regulation of Large Calcium-activated Potassium Channels by Protein Phosphatase 2A*. THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, No. 15, (1997).
84. Lijun Tian, Hans-Guenther Knaus‡, and Michael J. Shipston§: Glucocorticoid Regulation of Calcium-activated Potassium Channels
Mediated by Serine/Threonine Protein Phosphatase*. THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 273, No. 22, (1998).
85. Duane D. Hall,‡ Joel A. Feekes,‡ Aruni S. Arachchige Don,‡ Mei Shi,‡ Jawed Hamid,§ Lina Chen,§ Stefan Strack,‡Gerald W. Zamponi,§ Mary C. Horne,‡ and Johannes W. Hell*,‡: Binding of Protein Phosphatase 2A to the L-Type Calcium Channel Cav1.2 next to Ser1928, Its Main PKA Site, Is Critical for Ser1928 Dephosphorylation†. Biochemistry, 45:3448-3459, (2006).
86. Hélène A. Widmer, Iain C. M. Rowe and Michael J. Shipston: Conditional protein phosphorylation regulates BK channel activity in rat cerebellar Purkinje neurons. J. Physiol. 552:379-391, (2003).