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. 2006 Apr 5;11(3):296–305. doi: 10.1111/j.1750-3639.2001.tb00400.x

p73 is not Mutated in Meningiomas as Determined with a Functional Yeast Assay but p73 Expression Increases with Tumor Grade

Michimasa Nozaki 1,2, Mitsuhiro Tada 3, Haruhiko Kashiwazaki 3, Marie‐France Hamou 1, Annie‐Claire Diserens 1, Yumiko Shinohe 2, Yutaka Sawamura 2, Yoshinobu Iwasaki 2, Nicolas de Tribolet 1, Monika E Hegi 1,✉
PMCID: PMC8098457  PMID: 11414472

Abstract

The p53 gene is normally wild type in meningiomas. Since all three members of the p53 gene family recognize the same DNA sequence, tumors containing wild type p53 could decrease transactivation of p53 target genes by mutating either p63 or p73. In meningiomas the most likely target is p73, because loss of heterozygosity of the chromosomal band containing p73 is the commonest genetic lesion in these tumors. To screen p73 for mutations we have developed a functional assay which tests the ability of p73 to activate transcription from a p53‐responsive promoter in yeast. The assay correctly identified p73 mutants with mutations equivalent to hotspot mutations in p53, demonstrating that the assay can detect transcriptionally inactive p73. No mutations in p73 were identified in meningiomas. p73 RNA level was higher in more advanced tumors, but there was no correlation between the expression level of p73 and p21, a known p53 target gene. The yeast assay was also used to measure the intrinsic sensitivity of the p73 protein to mutagenesis. Like p53, p73 is exceptionally easy to inactivate as a transcription factor by point mutation. Taken together, these results indicate that p53 and p73 serve very different functions in tumors.

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References

  • 1. Agami R, Blandino G, Oren M, Shaul Y (1999) Interaction of c‐Abl and p73alpha and their collaboration to induce apoptosis. Nature 399: 809–813. [DOI] [PubMed] [Google Scholar]
  • 2. Baker SJ, Markowitz S, Fearon ER, Willson JKU, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wild‐type p53. Science 249: 912–915. [DOI] [PubMed] [Google Scholar]
  • 3. Bostrom J, Muhlbauer A, Reifenberger G (1997) Deletion mapping of the short arm of chromosome 1 identifies a common region of deletion distal to D1S496 in human meningiomas. Acta Neuropathol (Berl) 94: 479–485. [DOI] [PubMed] [Google Scholar]
  • 4. Cai YC, Yang GY, Nie Y, Wang LD, Zhao X, Song YL, Seril DN, Liao J, Xing EP, Yang CS (2000) Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53. Carcinogenesis 21: 683–689. [DOI] [PubMed] [Google Scholar]
  • 5. Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH (1999) Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. Cancer Res 59: 2791–2793. [PubMed] [Google Scholar]
  • 6. Chi SW, Ayed A, Arrowsmith CH (1999) Solution structure of a conserved C‐terminal domain of p73 with structural homology to the SAM domain. Embo J 18: 4438–4445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. De Laurenzi V, Costanzo A, Barcaroli D, Terrinoni A, Falco M, Annicchiarico‐Petruzzelli M, Levrero M, Melino G (1998) Two new p73 splice variants, gamma and delta, with different transcriptional activity. J Exp Med 188: 1763–1768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. De Laurenzi VD, Catani MV, Terrinoni A, Corazzari M, Melino G, Costanzo A, Levrero M, Knight RA (1999) Additional complexity in p73: induction by mitogens in lymphoid cells and identification of two new splicing variants epsilon and zeta (letter). Cell Death Differ 6: 389–390. [DOI] [PubMed] [Google Scholar]
  • 9. Di Como CJ, Gaiddon C, Prives C (1999) p73 function is inhibited by tumor‐derived p53 mutants in mammalian cells. Mol Cell Biol 19: 1438–1449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L, Benhattar J, et al. (1995) A simple p53 functional assay for screening cell lines, blood, and tumors. Proc Natl Acad Sci USA 92: 3963–3967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Ishioka C, Friend SH, Iggo R (1994) A rapid PCR fidelity assay. Nucleic Acids Res 22: 3259–3260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG, Jr. , Levrero M, Wang JY (1999) The tyrosine kinase c‐Abl regulates p73 in apoptotic response to cisplatin‐induced DNA damage. Nature 399: 806–809. [DOI] [PubMed] [Google Scholar]
  • 13. Herath NI, Kew MC, Whitehall VL, Walsh MD, Jass JR, Khanna KK, Young J, Powell LW, Leggett BA, Macdonald GA (2000) p73 is up‐regulated in a subset of hepatocellular carcinomas. Hepatology 31: 601–605. [DOI] [PubMed] [Google Scholar]
  • 14. Ichimiya S, Nimura Y, Kageyama H, Takada N, Sunahara M, Shishikura T, Nakamura Y, Sakiyama S, Seki N, Ohira M, Kaneko Y, McKeon F, Caput D, Nakagawara A (1999) p73 at chromosome 1 p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. Oncogene 18: 1061–1066. [DOI] [PubMed] [Google Scholar]
  • 15. Ikawa S, Nakagawara A, Ikawa Y (1999) p53 family genes: structural comparison, expression and mutation. Cell Death Differ 6: 1154–1161. [DOI] [PubMed] [Google Scholar]
  • 16. Ishino S, Hashimoto N, Fushiki S, Date K, Mori T, Fujimoto M, Nakagawa Y, Ueda S, Abe T, Inazawa J (1998) Loss of material from chromosome arm 1p during malignant progression of meningioma revealed by fluorescent in situ hybridization. Cancer 83: 360–366. [PubMed] [Google Scholar]
  • 17. Ishioka C, Frebourg T, Yan YX, Vidal M, Friend SH, Schmidt S, Iggo R (1993) Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet 5: 124–129. [DOI] [PubMed] [Google Scholar]
  • 18. Jost CA, Marin MC, Kaelin WG, Jr. (1997) p73 is a simian [correction of human] p53‐related protein that can induce apoptosis (published erratum appears in Nature 1999 Jun 24;399[6738]:817). Cell 90: 829–832. [DOI] [PubMed] [Google Scholar]
  • 19. Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F, Caput D (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Nature 389: 122–123. [DOI] [PubMed] [Google Scholar]
  • 20. Kleihues P, Cavenee WK (eds) (2000). Pathology and Genetics of Tumours of the Nervous System. Lyon : IARC Press. [Google Scholar]
  • 21. Lamszus K, Kluwe L, Matschke J, Meissner H, Laas R, Westphal M (1999) Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. Cancer Genet Cytogen 110: 103–110. [DOI] [PubMed] [Google Scholar]
  • 22. Lissy NA, Davis PK, Irwin M, Kaelin WG, Dowdy SF (2000) A common E2F‐1 and p73 pathway mediates cell death induced by TCR activation. Nature 407: 642–645. [DOI] [PubMed] [Google Scholar]
  • 23. Louis DN, Ramesh V, Gusella JF (1995) Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathol 5: 163–172. [DOI] [PubMed] [Google Scholar]
  • 24. Ng SW, Yiu GK, Liu Y, Huang LW, Palnati M, Jun SH, Berkowitz RS, Mok SC (2000) Analysis of p73 in human borderline and invasive ovarian tumor. Oncogene 19: 1885–1890. [DOI] [PubMed] [Google Scholar]
  • 25. Nozaki M, Tada M, Matsumoto R, Sawamura Y, Abe H, Iggo RD (1998) Rare occurrence of inactivating p53 gene mutations in primary non‐astrocytic tumors of the central nervous system: reappraisal by yeast functional assay. Acta Neuropathol (Berl) 95: 291–296. [DOI] [PubMed] [Google Scholar]
  • 26. Pozniak CD, Radinovic S, Yang A, McKeon F, Kaplan DR, Miller FD (2000) An anti‐apoptotic role for the p53 family member, p73, during developmental neuron death. Science 289: 304–306. [DOI] [PubMed] [Google Scholar]
  • 27. Ruttledge MH, Sarrazin J, Rangaratnam S, Phelan CM, Twist E, Merel P, Delattre O, Thomas G, Nordenskjold M, Collins VP, et al. (1994) Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 6: 180–184. [DOI] [PubMed] [Google Scholar]
  • 28. Scaruffi P, Casciano I, Masiero L, Basso G, Romani M, Tonini GP (2000) Lack of p73 expression in mature B‐ALL and identification of three new splicing variants restricted to pre B and C‐ALL indicate a role of p73 in B cell ALL differentiation (letter). Leukemia 14: 518–519. [DOI] [PubMed] [Google Scholar]
  • 29. Simon M, von Deimling A, Larson JJ, Wellenreuther R, Kaskel P, Waha A, Warnick RE, Tew JM, Jr. , Menon AG (1995) Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res 55: 4696–4701. [PubMed] [Google Scholar]
  • 30. Stiewe T, Putzer BM (2000) Role of the p53‐homologue p73 in E2F1‐induced apoptosis. Nat Genet 26: 464–469. [DOI] [PubMed] [Google Scholar]
  • 31. Sulman EP, Dumanski JP, White PS, Zhao H, Maris JM, Mathiesen T, Bruder C, Cnaan A, Brodeur GM (1998) Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity. Cancer Res 58: 3226–3230. [PubMed] [Google Scholar]
  • 32. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, et al. (1993) A novel moesin‐, ezrin‐, radixin‐like gene is a candidate for the neurofibromatosis 2 tumor suppressor (published erratum appears in Cell 1993 Nov 19;75[4]:826). Cell 72: 791–800. [DOI] [PubMed] [Google Scholar]
  • 33. Vikhanskaya F, Marchini S, Marabese M, Galliera E, Broggini M (2001) P73a overexpression is associated with resistance to treatment with DNA‐damaging agents in a human ovarian cancer cell line. Cancer Res 61: 935–938. [PubMed] [Google Scholar]
  • 34. Weber RG, Bostrom J, Wolter M, Baudis M, Collins VP, Reifenberger G, Lichter P (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94: 14719–14724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Wellenreuther R, Kraus JA, Lenartz D, Menon AG, Schramm J, Louis DN, Ramesh V, Gusella JF, Wiestler OD, von Deimling A (1995) Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol 146: 827–832. [PMC free article] [PubMed] [Google Scholar]
  • 36. Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F, Caput D (2000) p73‐deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404: 99–103. [DOI] [PubMed] [Google Scholar]
  • 37. Yoshikawa H, Nagashima M, Khan MA, McMenamin MG, Hagiwara K, Harris CC (1999) Mutational analysis of p73 and p53 in human cancer cell lines. Oncogene 18: 3415–3421. [DOI] [PubMed] [Google Scholar]
  • 38. Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S, Weichselbaum R, Kufe D (1999) p73 is regulated by tyrosine kinase c‐Abl in the apoptotic response to DNA damage (published erratum appears in Nature 1999 Aug 19;400[6746]:792). Nature 399: 814–817. [DOI] [PubMed] [Google Scholar]
  • 39. Zaika AI, Kovalev S, Marchenko ND, Moll UM (1999) Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res 59: 3257–3263. [PubMed] [Google Scholar]

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