Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May;80(5-6):670–675. doi: 10.1038/sj.bjc.6690408

Loss of functional pRB is not a ubiquitous feature of B-cell malignancies

A J Sinclair 1, V Frost 1
PMCID: PMC2362291  PMID: 10360642

Abstract

Human cancers frequently sustain genetic mutations that alter the function of their G1 cell cycle control check point. These include changes to the retinoblastoma gene and to the genes that regulate its phosphorylation, such as the cyclin-dependent kinase inhibitor p16INK4a. Altered expression of retinoblastoma protein (pRb) is associated with non-Hodgkin's lymphoma, particularly centroblastic and Burkitt's lymphomas. pRb is expressed in normal B-cells and its regulatory phosphorylation pathway is activated in response to a variety of stimuli. Since human B-lymphoma-derived cell lines are often used as in vitro model systems to analyse the downstream effects of signal transduction, we examined the functional status of pRb in a panel of human B-cell lines. We identified eleven cell lines which express the hyperphosphorylated forms of pRb. Furthermore, we suggest that the pRb protein appears to be functional in these cell lines. © 1999 Cancer Research Campaign

Keywords: retinoblastoma protein, cdkI, p16INK4a, tumour suppressor, Burkitt's lymphoma, Epstein–Barr virus

Full Text

The Full Text of this article is available as a PDF (146.8 KB).

Selected References

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

  1. Aagaard L., Lukas J., Bartkova J., Kjerulff A. A., Strauss M., Bartek J. Aberrations of p16Ink4 and retinoblastoma tumour-suppressor genes occur in distinct sub-sets of human cancer cell lines. Int J Cancer. 1995 Mar 29;61(1):115–120. doi: 10.1002/ijc.2910610120. [DOI] [PubMed] [Google Scholar]
  2. Alevizopoulos K., Vlach J., Hennecke S., Amati B. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J. 1997 Sep 1;16(17):5322–5333. doi: 10.1093/emboj/16.17.5322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allday M. J., Sinclair A., Parker G., Crawford D. H., Farrell P. J. Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. EMBO J. 1995 Apr 3;14(7):1382–1391. doi: 10.1002/j.1460-2075.1995.tb07124.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arvanitakis L., Yaseen N., Sharma S. Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. J Immunol. 1995 Aug 1;155(3):1047–1056. [PubMed] [Google Scholar]
  5. Banks P. M., Chan J., Cleary M. L., Delsol G., De Wolf-Peeters C., Gatter K., Grogan T. M., Harris N. L., Isaacson P. G., Jaffe E. S. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. Am J Surg Pathol. 1992 Jul;16(7):637–640. doi: 10.1097/00000478-199207000-00001. [DOI] [PubMed] [Google Scholar]
  6. Bartek J., Bartkova J., Lukas J. The retinoblastoma protein pathway and the restriction point. Curr Opin Cell Biol. 1996 Dec;8(6):805–814. doi: 10.1016/s0955-0674(96)80081-0. [DOI] [PubMed] [Google Scholar]
  7. Bartkova J., Lukas J., Guldberg P., Alsner J., Kirkin A. F., Zeuthen J., Bartek J. The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res. 1996 Dec 1;56(23):5475–5483. [PubMed] [Google Scholar]
  8. Bartkova J., Lukas J., Strauss M., Bartek J. Cyclin D3: requirement for G1/S transition and high abundance in quiescent tissues suggest a dual role in proliferation and differentiation. Oncogene. 1998 Aug 27;17(8):1027–1037. doi: 10.1038/sj.onc.1202016. [DOI] [PubMed] [Google Scholar]
  9. Bates S., Bonetta L., MacAllan D., Parry D., Holder A., Dickson C., Peters G. CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1. Oncogene. 1994 Jan;9(1):71–79. [PubMed] [Google Scholar]
  10. Cannell E. J., Farrell P. J., Sinclair A. J. Epstein-Barr virus exploits the normal cell pathway to regulate Rb activity during the immortalisation of primary B-cells. Oncogene. 1996 Oct 3;13(7):1413–1421. [PubMed] [Google Scholar]
  11. Clements G. B., Klein G., Povey S. Production by EBV infection of an EBNA-positive subline from an EBNA-negative human lymphoma cell line without detectable EBV DNA. Int J Cancer. 1975 Jul 15;16(1):125–133. doi: 10.1002/ijc.2910160114. [DOI] [PubMed] [Google Scholar]
  12. Cowell J. K., Hogg A. Genetics and cytogenetics of retinoblastoma. Cancer Genet Cytogenet. 1992 Nov;64(1):1–11. doi: 10.1016/0165-4608(92)90314-x. [DOI] [PubMed] [Google Scholar]
  13. Diller L., Kassel J., Nelson C. E., Gryka M. A., Litwak G., Gebhardt M., Bressac B., Ozturk M., Baker S. J., Vogelstein B. p53 functions as a cell cycle control protein in osteosarcomas. Mol Cell Biol. 1990 Nov;10(11):5772–5781. doi: 10.1128/mcb.10.11.5772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Farrell P. J., Allan G. J., Shanahan F., Vousden K. H., Crook T. p53 is frequently mutated in Burkitt's lymphoma cell lines. EMBO J. 1991 Oct;10(10):2879–2887. doi: 10.1002/j.1460-2075.1991.tb07837.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gregory C. D., Rowe M., Rickinson A. B. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol. 1990 Jul;71(Pt 7):1481–1495. doi: 10.1099/0022-1317-71-7-1481. [DOI] [PubMed] [Google Scholar]
  16. Hall M., Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res. 1996;68:67–108. doi: 10.1016/s0065-230x(08)60352-8. [DOI] [PubMed] [Google Scholar]
  17. Hara E., Smith R., Parry D., Tahara H., Stone S., Peters G. Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol. 1996 Mar;16(3):859–867. doi: 10.1128/mcb.16.3.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harris N. L., Jaffe E. S., Stein H., Banks P. M., Chan J. K., Cleary M. L., Delsol G., De Wolf-Peeters C., Falini B., Gatter K. C. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994 Sep 1;84(5):1361–1392. [PubMed] [Google Scholar]
  19. He J., Olson J. J., James C. D. Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. Cancer Res. 1995 Nov 1;55(21):4833–4836. [PubMed] [Google Scholar]
  20. Herman J. G., Merlo A., Mao L., Lapidus R. G., Issa J. P., Davidson N. E., Sidransky D., Baylin S. B. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995 Oct 15;55(20):4525–4530. [PubMed] [Google Scholar]
  21. Herwig S., Strauss M. The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. Eur J Biochem. 1997 Jun 15;246(3):581–601. doi: 10.1111/j.1432-1033.1997.t01-2-00581.x. [DOI] [PubMed] [Google Scholar]
  22. Hinuma Y., Konn M., Yamaguchi J., Wudarski D. J., Blakeslee J. R., Jr, Grace J. T., Jr Immunofluorescence and herpes-type virus particles in the P3HR-1 Burkitt lymphoma cell line. J Virol. 1967 Oct;1(5):1045–1051. doi: 10.1128/jvi.1.5.1045-1051.1967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Holder M. J., Wang H., Milner A. E., Casamayor M., Armitage R., Spriggs M. K., Fanslow W. C., MacLennan I. C., Gregory C. D., Gordon J. Suppression of apoptosis in normal and neoplastic human B lymphocytes by CD40 ligand is independent of Bc1-2 induction. Eur J Immunol. 1993 Sep;23(9):2368–2371. doi: 10.1002/eji.1830230948. [DOI] [PubMed] [Google Scholar]
  24. Hollyoake M., Stühler A., Farrell P., Gordon J., Sinclair A. The normal cell cycle activation program is exploited during the infection of quiescent B lymphocytes by Epstein-Barr virus. Cancer Res. 1995 Nov 1;55(21):4784–4787. [PubMed] [Google Scholar]
  25. Itoh N., Kakehi Y., Akao T., Kinoshita H., Okada Y., Yoshida O. Concomitant presence of p16/cyclin-dependent kinase 4 and cyclin D/cyclin-dependent kinase 4 complexes in LNCaP prostatic cancer cell line. Jpn J Cancer Res. 1997 Mar;88(3):229–233. doi: 10.1111/j.1349-7006.1997.tb00371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kelley M. J., Otterson G. A., Kaye F. J., Popescu N. C., Johnson B. E., Dipaolo J. A. CDKN2 in HPV-positive and HPV-negative cervical-carcinoma cell lines. Int J Cancer. 1995 Oct 9;63(2):226–230. doi: 10.1002/ijc.2910630214. [DOI] [PubMed] [Google Scholar]
  27. Kempkes B., Spitkovsky D., Jansen-Dürr P., Ellwart J. W., Kremmer E., Delecluse H. J., Rottenberger C., Bornkamm G. W., Hammerschmidt W. B-cell proliferation and induction of early G1-regulating proteins by Epstein-Barr virus mutants conditional for EBNA2. EMBO J. 1995 Jan 3;14(1):88–96. doi: 10.1002/j.1460-2075.1995.tb06978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Khleif S. N., DeGregori J., Yee C. L., Otterson G. A., Kaye F. J., Nevins J. R., Howley P. M. Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4350–4354. doi: 10.1073/pnas.93.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. King W., Thomas-Powell A. L., Raab-Traub N., Hawke M., Kieff E. Epstein-Barr virus RNA. V. Viral RNA in a restringently infected, growth-transformed cell line. J Virol. 1980 Nov;36(2):506–518. doi: 10.1128/jvi.36.2.506-518.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Klein G., Ehlin-Henriksson B., Schlossman S. F. Induction of an activated b lymphocyte-associated surface moiety defined by the B2 monoclonal antibody by ebv conversion of an EBV-negative lymphoma line (Ramos): differential effect of transforming (B95-8) and nontransforming (P3HR-1) EBV substrains. J Immunol. 1983 Apr;130(4):1985–1989. [PubMed] [Google Scholar]
  31. Klein G., Giovanella B., Westman A., Stehlin J. S., Mumford D. An EBV-genome-negative cell line established from an American Burkitt lymphoma; receptor characteristics. EBV infectibility and permanent conversion into EBV-positive sublines by in vitro infection. Intervirology. 1975;5(6):319–334. doi: 10.1159/000149930. [DOI] [PubMed] [Google Scholar]
  32. Klein R. Priorities and the problems of planning. Br Med J. 1977 Oct 22;2(6094):1096–1097. doi: 10.1136/bmj.2.6094.1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Koh J., Enders G. H., Dynlacht B. D., Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature. 1995 Jun 8;375(6531):506–510. doi: 10.1038/375506a0. [DOI] [PubMed] [Google Scholar]
  34. Kratzke R. A., Otterson G. A., Lincoln C. E., Ewing S., Oie H., Geradts J., Kaye F. J. Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma. J Natl Cancer Inst. 1995 Dec 20;87(24):1870–1875. doi: 10.1093/jnci/87.24.1870. [DOI] [PubMed] [Google Scholar]
  35. Leone G., DeGregori J., Sears R., Jakoi L., Nevins J. R. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature. 1997 May 22;387(6631):422–426. doi: 10.1038/387422a0. [DOI] [PubMed] [Google Scholar]
  36. Li Y., Nichols M. A., Shay J. W., Xiong Y. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 1994 Dec 1;54(23):6078–6082. [PubMed] [Google Scholar]
  37. Ludlow J. W., DeCaprio J. A., Huang C. M., Lee W. H., Paucha E., Livingston D. M. SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family. Cell. 1989 Jan 13;56(1):57–65. doi: 10.1016/0092-8674(89)90983-5. [DOI] [PubMed] [Google Scholar]
  38. Lukas J., Bartkova J., Welcker M., Petersen O. W., Peters G., Strauss M., Bartek J. Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types. Oncogene. 1995 Jun 1;10(11):2125–2134. [PubMed] [Google Scholar]
  39. Lukas J., Herzinger T., Hansen K., Moroni M. C., Resnitzky D., Helin K., Reed S. I., Bartek J. Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev. 1997 Jun 1;11(11):1479–1492. doi: 10.1101/gad.11.11.1479. [DOI] [PubMed] [Google Scholar]
  40. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503–506. doi: 10.1038/375503a0. [DOI] [PubMed] [Google Scholar]
  41. MacDonald I., Wang H., Grand R., Armitage R. J., Fanslow W. C., Gregory C. D., Gordon J. Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines. Blood. 1996 Feb 1;87(3):1147–1154. [PubMed] [Google Scholar]
  42. Martínez J. C., Piris M. A., Sánchez-Beato M., Villuendas R., Orradre J. L., Algara P., Sánchez-Verde L., Martínez P. Retinoblastoma (Rb) gene product expression in lymphomas. Correlation with Ki67 growth fraction. J Pathol. 1993 Apr;169(4):405–412. doi: 10.1002/path.1711690404. [DOI] [PubMed] [Google Scholar]
  43. Merlo A., Herman J. G., Mao L., Lee D. J., Gabrielson E., Burger P. C., Baylin S. B., Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995 Jul;1(7):686–692. doi: 10.1038/nm0795-686. [DOI] [PubMed] [Google Scholar]
  44. Mittnacht S. Control of pRB phosphorylation. Curr Opin Genet Dev. 1998 Feb;8(1):21–27. doi: 10.1016/s0959-437x(98)80057-9. [DOI] [PubMed] [Google Scholar]
  45. Morgenbesser S. D., Williams B. O., Jacks T., DePinho R. A. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature. 1994 Sep 1;371(6492):72–74. doi: 10.1038/371072a0. [DOI] [PubMed] [Google Scholar]
  46. Musgrove E. A., Lilischkis R., Cornish A. L., Lee C. S., Setlur V., Seshadri R., Sutherland R. L. Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer. Int J Cancer. 1995 Nov 15;63(4):584–591. doi: 10.1002/ijc.2910630420. [DOI] [PubMed] [Google Scholar]
  47. Otterson G. A., Khleif S. N., Chen W., Coxon A. B., Kaye F. J. CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2'deoxycytidine. Oncogene. 1995 Sep 21;11(6):1211–1216. [PubMed] [Google Scholar]
  48. Otterson G. A., Kratzke R. A., Coxon A., Kim Y. W., Kaye F. J. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene. 1994 Nov;9(11):3375–3378. [PubMed] [Google Scholar]
  49. Palmero I., Holder A., Sinclair A. J., Dickson C., Peters G. Cyclins D1 and D2 are differentially expressed in human B-lymphoid cell lines. Oncogene. 1993 Apr;8(4):1049–1054. [PubMed] [Google Scholar]
  50. Palmero I., Peters G. Perturbation of cell cycle regulators in human cancer. Cancer Surv. 1996;27:351–367. [PubMed] [Google Scholar]
  51. Pan H., Griep A. E. Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development. Genes Dev. 1994 Jun 1;8(11):1285–1299. doi: 10.1101/gad.8.11.1285. [DOI] [PubMed] [Google Scholar]
  52. Parry D., Bates S., Mann D. J., Peters G. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J. 1995 Feb 1;14(3):503–511. doi: 10.1002/j.1460-2075.1995.tb07026.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Pokrovskaja K., Ehlin-Henriksson B., Bartkova J., Bartek J., Scuderi R., Szekely L., Wiman K. G., Klein G. Phenotype-related differences in the expression of D-type cyclins in human B cell-derived lines. Cell Growth Differ. 1996 Dec;7(12):1723–1732. [PubMed] [Google Scholar]
  54. Pontén J., Saksela E. Two established in vitro cell lines from human mesenchymal tumours. Int J Cancer. 1967 Sep 15;2(5):434–447. doi: 10.1002/ijc.2910020505. [DOI] [PubMed] [Google Scholar]
  55. Scheffner M., Münger K., Byrne J. C., Howley P. M. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5523–5527. doi: 10.1073/pnas.88.13.5523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  57. Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. J. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995 Feb 1;55(3):505–509. [PubMed] [Google Scholar]
  58. Shapiro G. I., Park J. E., Edwards C. D., Mao L., Merlo A., Sidransky D., Ewen M. E., Rollins B. J. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res. 1995 Dec 15;55(24):6200–6209. [PubMed] [Google Scholar]
  59. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
  60. Shivdasani R. A., Hess J. L., Skarin A. T., Pinkus G. S. Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin's lymphoma. J Clin Oncol. 1993 Apr;11(4):802–111. doi: 10.1200/JCO.1993.11.4.802. [DOI] [PubMed] [Google Scholar]
  61. Sinclair A. J., Fenton M., Delikat S. Interactions between Epstein-Barr virus and the cell cycle control machinery. Histol Histopathol. 1998 Apr;13(2):461–467. doi: 10.14670/HH-13.461. [DOI] [PubMed] [Google Scholar]
  62. Sinclair A. J., Jacquemin M. G., Brooks L., Shanahan F., Brimmell M., Rowe M., Farrell P. J. Reduced signal transduction through glucocorticoid receptor in Burkitt's lymphoma cell lines. Virology. 1994 Mar;199(2):339–353. doi: 10.1006/viro.1994.1132. [DOI] [PubMed] [Google Scholar]
  63. Sinclair A. J., Palmero I., Peters G., Farrell P. J. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO J. 1994 Jul 15;13(14):3321–3328. doi: 10.1002/j.1460-2075.1994.tb06634.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Szekely L., Pokrovskaja K., Jiang W. Q., Selivanova G., Löwbeer M., Ringertz N., Wiman K. G., Klein G. Resting B-cells, EBV-infected B-blasts and established lymphoblastoid cell lines differ in their Rb, p53 and EBNA-5 expression patterns. Oncogene. 1995 May 4;10(9):1869–1874. [PubMed] [Google Scholar]
  65. Takada K. Cross-linking of cell surface immunoglobulins induces Epstein-Barr virus in Burkitt lymphoma lines. Int J Cancer. 1984 Jan 15;33(1):27–32. doi: 10.1002/ijc.2910330106. [DOI] [PubMed] [Google Scholar]
  66. Tam S. W., Shay J. W., Pagano M. Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. Cancer Res. 1994 Nov 15;54(22):5816–5820. [PubMed] [Google Scholar]
  67. Templeton D. J., Park S. H., Lanier L., Weinberg R. A. Nonfunctional mutants of the retinoblastoma protein are characterized by defects in phosphorylation, viral oncoprotein association, and nuclear tethering. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3033–3037. doi: 10.1073/pnas.88.8.3033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Weide R., Tiemann M., Pflüger K. H., Köppler H., Parvizl B., Wacker H. H., Kreipe H. H., Havemann K., Parwaresch M. R. Altered expression of the retinoblastoma gene product in human high grade non-Hodgkin's lymphomas. Leukemia. 1994 Jan;8(1):97–101. [PubMed] [Google Scholar]
  69. Weinberg R. A. The retinoblastoma gene and gene product. Cancer Surv. 1992;12:43–57. [PubMed] [Google Scholar]
  70. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  71. Welcker M., Lukas J., Strauss M., Bartek J. Enhanced protein stability: a novel mechanism of D-type cyclin over-abundance identified in human sarcoma cells. Oncogene. 1996 Jul 18;13(2):419–425. [PubMed] [Google Scholar]
  72. Xu H. J., Hu S. X., Hashimoto T., Takahashi R., Benedict W. F. The retinoblastoma susceptibility gene product: a characteristic pattern in normal cells and abnormal expression in malignant cells. Oncogene. 1989 Jun;4(6):807–812. [PubMed] [Google Scholar]

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

RESOURCES