|
|
||||
|
|
||||
|
||||
Neuropathology |
Department of Tumor Virology, Heinrich-Pette-Institute of Experimental Virology and Immunology at the University of Hamburg, Martinistr. 52, 20251 Hamburg, Germany (O.S., W.D., W.B.); and Department of Neuropathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (C.H., K.L.)
2 Address correspondence to Wolfgang Bohn, Heinrich-Pette-Institut, Martinistr. 52, 20251 Hamburg, Germany.
Abstract
Cytoplasmic accumulation of wild-type p53 in tumor cells indicates that the tumor suppressor is inactive with regard to growth suppressive functions. Whether this occurs randomly during tumor development or characterizes a certain tumor cell subset is not known. Here we assayed primary glioblastomas for expression and subcellular localization of p53 and determined a correlation with expression of intermediate filament proteins characterizing glial cell development. Sixty-nine percent of the tumors were p53 positive in immunohistochemistry. A significant number of tumors (23%) accumulated wild-type p53 in the cytoplasm, which correlated with the presence of vimentin and glial fibrillary acidic protein, except for 1 case. Tumors with exclusive nuclear p53 contained none or only one of these intermediate filament proteins. In an alternative approach, tumors positive for glial fibrillary acidic protein were screened for expression of p53 and vimentin. Thirty-eight percent of these tumors showed cytoplasmic p53, and all of those also expressed vimentin. Tumors with only nuclear p53 were vimentin negative, except for 1 case. No mutation was detected in p53 exons 5 to 8 in tumors with cytoplasmic p53, suggesting that they express wild-type p53. The data indicate that a cytoplasmic accumulation of wild-type p53 in human primary glioblastomas correlates with a certain intermediate filament protein expression, suggesting that it identifies a certain subset of tumors.
References
Ali, I.U., Schweitzer, J.B., Ikejiri, B., Saxena, A., Robertson,
J.T., and Oldfield, E.H. (1994) Heterogeneity of subcellular
localization of p53 protein in human glioblastomas. Cancer
Res. 54,1
-5.
Bohn, W., Röser, K., Hohenberg, H., Mannweiler, K., and Traub, P. (1993) Cytoskeleton architecture of C6 glioma cell subclones differing in intermediate filament protein expression. J. Struct. Biol. 111,48 -58.[CrossRef][Web of Science][Medline]
Collins, V.P. (1999) Progression as exemplified by human astrocytic tumors. Semin. Cancer Biol. 9, 267-276.[CrossRef][Web of Science][Medline]
Cosgrove, M., Fitzgibbons, P.L., Sherrod, A., Chandrasoma, P.T., and Martin, S.E. (1989) Intermediate filament expression in astrocytic neoplasms. Am. J. Surg. Pathol. 13,141 -145.[Web of Science][Medline]
Dahlstrand, J., Collins, V.P., and Lehndahl, U. (1992)
Expression of the class VI intermediate filament nestin in human central
nervous system tumors. Cancer Res.
52,5334
-5341.
Eizenberg,O., Faber-Elman,A., Gottlieb, E., Oren, M., Rotter, V., and Schwartz, M. (1996) P53 plays a regulatory role in differentiation and apoptosis of central nervous system-associated cells. Mol. Cell. Biol. 16,5178 -5185.[Abstract]
Franke, W.W., Schmid, E., Schiller, D.L., Winter, S., Jarasch, E.D., Moll, R., Denk, H., Jackson, B.W., and Illmensee, K. (1982) Differentiation-related patterns of expression of proteins of intermediate-size filaments in tissues and cultured cells. Cold Spring Harb. Symp. Quant. Biol. 46,431 -453.
Fulci, G. Ishii, N., and Van Meir, E.G. (1998) P53 and brain tumors: From gene mutations to gene therapy. Brain Pathol. 8,599 -613.[Web of Science][Medline]
Goldman, S.C, Chen, C.-Y., Lansing, T.J., Gilmer, T.M., and Kastan, M.B. (1996) The p53 signal transduction pathway is intact in human neuroblastoma despite cytoplasmic localization. Am. J. Pathol. 148,1381 -1385.[Abstract]
Hagel, C., Schwartz, P., Laas, R., and Stavrou, D.K. (1995) Comparison of four proliferation markers and their significance for evaluation of tumor dignity in intracranial tumors. Int. J. Oncol. 7,107 -113.
Hagel, C., Laking, G., Laas, R., Scheil, S., Jung, R., Milde-Langosch, K., and Stavrou, D.K. (1996) Demonstration of p53 protein and TP53 gene mutations in oligodendrogliomas. Eur. J. Cancer 32A,2242 -2248.[CrossRef]
Hartung, J., Elpelt, B., and Klösener, K.-H. (Eds.) (1999) Statistik. Twelfth edition. München, Germany: Oldenbourg Verlag.
Herpers, M.J., Ramaekers,F.C., Aldeweireldt,J., Moesker, O., and Slooff, J. (1986) Co-expression of glial fibrillary acidic protein- and vimentin-type intermediate filaments in human astrocytomas. Acta Neuropathol. (Berl.) 70,333 -339.[CrossRef][Medline]
Hirato, J., Nakazato, Y., and Ogawa, A. (1994) Expression of non-glial intermediate filament proteins in gliomas. Clin. Neuropathol. 13,1 -11.[Web of Science][Medline]
Ho, C.L., and Liem, R.K. (1996) Intermediate filaments in the nervous system: Implications in cancer. Cancer Metastasis Rev. 15,483 -497.[CrossRef][Web of Science][Medline]
Hussain, S.P., Hollstein, M.H., and Harris, C.C. (2000) P53 tumor suppressor gene: At the crossroads of molecular carcinogenesis, molecular epidemiology, and human risk assessment. Ann. N.Y. Acad. Sci. 919, 79-85.[Medline]
Janus, F., Albrechtsen, N., Dornreiter, I., Wiesmüller, L., Grosse, F., and Deppert, W. (1999) The dual role model for p53 in maintaining genomic integrity. Cell. Mol. Life Sci. 55, 12-27.[CrossRef][Web of Science][Medline]
Kleihues, P., and Cavenee, W.K. (Eds.) (2000) Pathology and Genetics of Tumors of the Nervous System. Lyon: IARC Press.
Klotzsche, O., Etzrodt, D., Hohenberg, H., Bohn, W., and Deppert, W. (1998) Cytoplasmic retention of mutant tsp53 is dependent on an intermediate filament protein (vimentin) scaffold. Oncogene 16,3423 -3434.[CrossRef][Web of Science][Medline]
Lee, J.C., Mayer-Proschel, M., and Rao, M.S. (2000) Gliogenesis in the central nervous system. Glia 30,105 -121.[CrossRef][Web of Science][Medline]
Levine, A.J. (1997) p53, the cellular gatekeeper for growth and division. Cell 88,323 -331.[CrossRef][Web of Science][Medline]
Louis, D.N., Von Deimling, A., Chung, R.Y., Rubio, M.P., Whaley, J.M., Eibl, R.H., Ohgaki, H., Wiestler, O.D., Thor, A.D., and Seizinger, B.R. (1993) Comparative study of p53 gene and protein alterations in human astrocytic tumors. J. Neuropathol. Exp. Neurol. 52, 31-38.[Web of Science][Medline]
Mashiyama, S., Murakami, Y., Yoshimoto, T., Sekiya, T., and Hayashi, K. (1991) Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 6,1313 -1318.[Web of Science][Medline]
Messam, C.A., Hou, J., and Major, E.O. (2000) Coexpression of nestin in neural and glial cells in the developing human CNS defined by a human-specific anti-nestin antibody. Exp. Neurol. 161,585 -596.[CrossRef][Web of Science][Medline]
Moll, U.M., Riou, G., and Levine, A.J. (1992) Two
distinct mechanisms alter p53 in breast cancer: Mutation and nuclear
exclusion. Proc. Natl. Acad. Sci. U.S.A.
89,7262
-7266.
Röser, K., Bohn, W., Giese, G., and Mannweiler, K. (1991) Subclones of C6 rat glioma cells differing in intermediate filament protein expression. Exp. Cell Res. 197,200 -206.[CrossRef][Web of Science][Medline]
Rubio, M.P., Von Deimling, A., Yandell, D.W., Wiestler, O.D.,
Gusella, J.F., and Louis, D.N. (1993) Accumulation of wild type
p53 protein in human astrocytomas. Cancer Res.
53,3465
-3467.
Sabapathy, K., Klemm, M., Jaenisch, R., and Wagner, E.F. (1997) Regulation of ES cell differentiation by functional and conformational modulation of p53. EMBO J. 16,6217 -6229.[CrossRef][Web of Science][Medline]
Sallinen, S.L., Sallinen, P.K., Haapasalo, H.K., Helin, H.J.,
Helen, P.T., Schraml, P., Kallioniemi, O.P., and Kononen, J.
(2000) Identification of differentially expressed genes in human
gliomas by DNA microarray and tissue chip techniques. Cancer
Res. 60,6617
-6622.
Schiffer, D., Giordana, M.T., Mauro, A., Migheli, A., Germano, I., and Giaccone, G. (1986) Immunohistochemical demonstration of vimentin in human cerebral tumors. Acta Neuropathol. (Berl.) 70,209 -219.[CrossRef][Medline]
Sidransky, D., Mikkelsen, T., Schwechheimer, K., Rosenblum, M.L., Cavenee, W., and Vogelstein, B. (1992) Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355,846 -847.[CrossRef][Medline]
Spandau, D.F. (1994) Distinct conformations of p53 are observed at different stages of keratinocyte differentiation. Oncogene 9,1861 -1868.[Web of Science][Medline]
Van Lookeren Campagne, M., and Gill, R. (1998) Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: Comparison with expression of the cell cycle regulators p21Waf1/Cip1, p27Kip1, p57Kip2, p16Ink4a, cyclin G1, and the proto-oncogene Bax. J. Comp. Neurol. 397,181 -198.[CrossRef][Web of Science][Medline]
Vital, A., Loiseau, H., Kantor, G., Daucourt, V., Chene, G., Cohadon, F., Rougier, A., Rivel, J., and Vital, C. (1998) P53 expression in grade II astrocytomas: Immunohistochemical study of 100 cases with long-term followup. Pathol. Res. Pract. 194,831 -836.[Web of Science][Medline]
Von Eckardstein, K., Gries, H., Bolik, E., Cervos-Navarro, J., Tschairkin, I.N., and Patt, S. (1997) p53 mutation and protein alteration in 50 gliomas: Retrospective study by DNA-sequencing techniques and immunohistochemistry. Histol. Histopathol. 12,611 -616.[Web of Science][Medline]
Watanabe, K., Tachibana, O., Sato, K., Yonekawa, Y., Kleihues, P., and Ohgaki, H. (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 6, 217-223.[Web of Science][Medline]
This article has been cited by other articles:
![]() |
F. Aloisio, J. M. Levine, and J. F. Edwards Immunohistochemical features of a feline spinal cord gemistocytic astrocytoma J Vet Diagn Invest, November 1, 2008; 20(6): 836 - 838. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. C. Kaul, S. Aida, T. Yaguchi, K. Kaur, and R. Wadhwa Activation of Wild Type p53 Function by Its Mortalin-binding, Cytoplasmically Localizing Carboxyl Terminus Peptides J. Biol. Chem., November 25, 2005; 280(47): 39373 - 39379. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|