Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(3):299–305. doi: 10.1038/bjc.1997.382

Nuclear accumulation of p53 correlates significantly with clinical features and inversely with the expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in pancreatic cancer.

N Harada 1, S Gansauge 1, F Gansauge 1, H Gause 1, S Shimoyama 1, T Imaizumi 1, T Mattfeld 1, M H Schoenberg 1, H G Beger 1
PMCID: PMC2224055  PMID: 9252195

Abstract

Recent studies have suggested a p53-independent expression of p21(WAF1/CIP1). We investigated the correlation between p53 overexpression and the expression of p21(WAF1/CIP1) in 57 patients with pancreatic adenocarcinoma. By means of reverse transcription and polymerase chain reaction (RT-PCR), we examined the mRNA levels of WAF1/CIP1 and compared them with the p53 status in 20 patients and in a further six pancreatic tumour cell lines. In pancreatic cancer tissues, immunohistological evaluation revealed a significant correlation between active p53 and p21(WAF1/CIP1) (P < 0.005) as well as WAF1/CIP1 mRNA expression (P < 0.005). This coherence was also evident in human pancreatic carcinoma cell lines. The analysis of p53 and p21(WAF1/CIP1) expression in relation to clinicopathological features revealed a significant correlation between p53 overexpression and tumour stage, tumour size, grading and lymph node metastases, whereas p21(WAF1/CIP1) expression correlated only with tumour size. We conclude that the expression of p21(WAF1/CIP1) normally depends on active p53, but that there may also exist p53-independent pathways of induction that reduce the correlation of p21(WAF1/CIP1) to clinicopathological features.

Full text

PDF
301

Images in this article

300Figure 1
on p.300
300Figure 2
on p.300
302Figure 4
on p.302
302Figure 5
on p.302
302Figure 6
on p.302

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akashi M., Hachiya M., Osawa Y., Spirin K., Suzuki G., Koeffler H. P. Irradiation induces WAF1 expression through a p53-independent pathway in KG-1 cells. J Biol Chem. 1995 Aug 11;270(32):19181–19187. doi: 10.1074/jbc.270.32.19181. [DOI] [PubMed] [Google Scholar]
  2. Barton C. M., Staddon S. L., Hughes C. M., Hall P. A., O'Sullivan C., Klöppel G., Theis B., Russell R. C., Neoptolemos J., Williamson R. C. Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer. 1991 Dec;64(6):1076–1082. doi: 10.1038/bjc.1991.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bourdon J. C., D'Errico A., Paterlini P., Grigioni W., May E., Debuire B. p53 protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation. Gastroenterology. 1995 Apr;108(4):1176–1182. doi: 10.1016/0016-5085(95)90217-1. [DOI] [PubMed] [Google Scholar]
  4. Børresen A. L., Hovig E., Smith-Sørensen B., Malkin D., Lystad S., Andersen T. I., Nesland J. M., Isselbacher K. J., Friend S. H. Constant denaturant gel electrophoresis as a rapid screening technique for p53 mutations. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8405–8409. doi: 10.1073/pnas.88.19.8405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Casey G., Yamanaka Y., Friess H., Kobrin M. S., Lopez M. E., Buchler M., Beger H. G., Korc M. p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett. 1993 May 14;69(3):151–160. doi: 10.1016/0304-3835(93)90168-9. [DOI] [PubMed] [Google Scholar]
  6. DiGiuseppe J. A., Redston M. S., Yeo C. J., Kern S. E., Hruban R. H. p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. Am J Pathol. 1995 Oct;147(4):884–888. [PMC free article] [PubMed] [Google Scholar]
  7. Dulić V., Kaufmann W. K., Wilson S. J., Tlsty T. D., Lees E., Harper J. W., Elledge S. J., Reed S. I. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell. 1994 Mar 25;76(6):1013–1023. doi: 10.1016/0092-8674(94)90379-4. [DOI] [PubMed] [Google Scholar]
  8. Finlay C. A., Hinds P. W., Tan T. H., Eliyahu D., Oren M., Levine A. J. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol. 1988 Feb;8(2):531–539. doi: 10.1128/mcb.8.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fisher D. E. Apoptosis in cancer therapy: crossing the threshold. Cell. 1994 Aug 26;78(4):539–542. doi: 10.1016/0092-8674(94)90518-5. [DOI] [PubMed] [Google Scholar]
  10. Forrester K., Lupold S. E., Ott V. L., Chay C. H., Band V., Wang X. W., Harris C. C. Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. Oncogene. 1995 Jun 1;10(11):2103–2111. [PubMed] [Google Scholar]
  11. Gansauge S., Gansauge F., Negri G., Galle P., Müller J., Nüssler A. K., Poch B., Beger H. G. The role of anti-p53-autoantibodies in pancreatic disorders. Int J Pancreatol. 1996 Jun;19(3):171–178. doi: 10.1007/BF02787365. [DOI] [PubMed] [Google Scholar]
  12. Hall P. A., Ray A., Lemoine N. R., Midgley C. A., Krausz T., Lane D. P. p53 immunostaining as a marker of malignant disease in diagnostic cytopathology. Lancet. 1991 Aug 24;338(8765):513–513. doi: 10.1016/0140-6736(91)90586-e. [DOI] [PubMed] [Google Scholar]
  13. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  14. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  15. Kastan M. B., Zhan Q., el-Deiry W. S., Carrier F., Jacks T., Walsh W. V., Plunkett B. S., Vogelstein B., Fornace A. J., Jr A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992 Nov 13;71(4):587–597. doi: 10.1016/0092-8674(92)90593-2. [DOI] [PubMed] [Google Scholar]
  16. Kern S. E., Kinzler K. W., Bruskin A., Jarosz D., Friedman P., Prives C., Vogelstein B. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991 Jun 21;252(5013):1708–1711. doi: 10.1126/science.2047879. [DOI] [PubMed] [Google Scholar]
  17. Lee C. S., Rush M., Charalambous D., Rode J. Immunohistochemical demonstration of the p53 tumour suppressor gene product in cancer of the pancreas and chronic pancreatitis. J Gastroenterol Hepatol. 1993 Sep-Oct;8(5):465–469. doi: 10.1111/j.1440-1746.1993.tb01550.x. [DOI] [PubMed] [Google Scholar]
  18. Melhem M. F., Law J. C., el-Ashmawy L., Johnson J. T., Landreneau R. J., Srivastava S., Whiteside T. L. Assessment of sensitivity and specificity of immunohistochemical staining of p53 in lung and head and neck cancers. Am J Pathol. 1995 May;146(5):1170–1177. [PMC free article] [PubMed] [Google Scholar]
  19. Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed] [Google Scholar]
  20. Nishio M., Koshikawa T., Kuroishi T., Suyama M., Uchida K., Takagi Y., Washimi O., Sugiura T., Ariyoshi Y., Takahashi T. Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers. J Clin Oncol. 1996 Feb;14(2):497–502. doi: 10.1200/JCO.1996.14.2.497. [DOI] [PubMed] [Google Scholar]
  21. Ory K., Legros Y., Auguin C., Soussi T. Analysis of the most representative tumour-derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. EMBO J. 1994 Aug 1;13(15):3496–3504. doi: 10.1002/j.1460-2075.1994.tb06656.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Parker S. B., Eichele G., Zhang P., Rawls A., Sands A. T., Bradley A., Olson E. N., Harper J. W., Elledge S. J. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science. 1995 Feb 17;267(5200):1024–1027. doi: 10.1126/science.7863329. [DOI] [PubMed] [Google Scholar]
  23. Pellegata N. S., Sessa F., Renault B., Bonato M., Leone B. E., Solcia E., Ranzani G. N. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res. 1994 Mar 15;54(6):1556–1560. [PubMed] [Google Scholar]
  24. Redston M. S., Caldas C., Seymour A. B., Hruban R. H., da Costa L., Yeo C. J., Kern S. E. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994 Jun 1;54(11):3025–3033. [PubMed] [Google Scholar]
  25. Scarpa A., Capelli P., Mukai K., Zamboni G., Oda T., Iacono C., Hirohashi S. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol. 1993 May;142(5):1534–1543. [PMC free article] [PubMed] [Google Scholar]
  26. Schwaller J., Koeffler H. P., Niklaus G., Loetscher P., Nagel S., Fey M. F., Tobler A. Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells. J Clin Invest. 1995 Mar;95(3):973–979. doi: 10.1172/JCI117806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Shiohara M., el-Deiry W. S., Wada M., Nakamaki T., Takeuchi S., Yang R., Chen D. L., Vogelstein B., Koeffler H. P. Absence of WAF1 mutations in a variety of human malignancies. Blood. 1994 Dec 1;84(11):3781–3784. [PubMed] [Google Scholar]
  28. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  29. Wynford-Thomas D. P53 in tumour pathology: can we trust immunocytochemistry? J Pathol. 1992 Apr;166(4):329–330. doi: 10.1002/path.1711660402. [DOI] [PubMed] [Google Scholar]
  30. Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. doi: 10.1038/366701a0. [DOI] [PubMed] [Google Scholar]
  31. du Breuil R. M., Patel J. M., Mendelow B. V. Quantitation of beta-actin-specific mRNA transcripts using xeno-competitive PCR. PCR Methods Appl. 1993 Aug;3(1):57–59. doi: 10.1101/gr.3.1.57. [DOI] [PubMed] [Google Scholar]
  32. el-Deiry W. S., Harper J. W., O'Connor P. M., Velculescu V. E., Canman C. E., Jackman J., Pietenpol J. A., Burrell M., Hill D. E., Wang Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed] [Google Scholar]
  33. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES