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Br J Cancer. 2000 November; 83(9): 1161–1167.
PMCID: PMC2363578

Cell cycle regulators p27 and pRb in lymphomas – correlation with histology and proliferative activity


The cell cycle is a complex event in which multiple regulator-proteins participate. The G 1/S checkpoint of the cell cycle is controlled by pRb protein, which functions in its hypophosphorylated form as a negative regulator of growth. p27 (Kip1), a member of CIP/KIP family of cyclin inhibitory proteins, participates in inhibition of forming complexes that allow pRb to phosphorylate and lead the cell into mitosis. The expression of these important cell cycle regulator proteins was studied in a total of 96 non-Hodgkin’s lymphoma (NHL) samples, which were classified according to the REAL classification. The expression of p27, pRb and the cell proliferation marker Ki-67 (MIB-1) was evaluated in lymphomas using immunohistochemistry. This study showed that there were coordinate changes in the expression of p27 and pRb in NHL. When compared to low-grade lymphomas, high-grade lymphomas showed significantly reduced expression of p27 and inversely pRb expression was increased (P < 0.001). Increase in expression of Ki-67 was parallel with pRb expression, and was mainly seen in cells that lacked p27 expression (P < 0.0001). This study suggests that changes in the control of the cell cycle closely relate to the pathobiology of NHL. © 2000 Cancer Research Campaign

Keywords: non-Hodgkin’s lymphoma, p27 (Kip1), pRb, Ki-67 (MIB-1)

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Selected References

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  • Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997 Feb;3(2):227–230. [PubMed]
  • Cinti C, Leoncini L, Nyongo A, Ferrari F, Lazzi S, Bellan C, Vatti R, Zamparelli A, Cevenini G, Tosi GM, et al. Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes. Am J Pathol. 2000 Mar;156(3):751–760. [PubMed]
  • Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A, te Riele H. Requirement for a functional Rb-1 gene in murine development. Nature. 1992 Sep 24;359(6393):328–330. [PubMed]
  • Geradts J, Andriko JW, Abbondanzo SL. Loss of tumor suppressor gene expression in high-grade but not low-grade non-Hodgkin's lymphomas. Am J Clin Pathol. 1998 Jun;109(6):669–674. [PubMed]
  • Graña X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene. 1995 Jul 20;11(2):211–219. [PubMed]
  • Hall M, Bates S, Peters G. Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins. Oncogene. 1995 Oct 19;11(8):1581–1588. [PubMed]
  • Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, et al. 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]
  • Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibitors in the development of cancer. Blood. 1995 Aug 1;86(3):841–854. [PubMed]
  • Hatta Y, Yamada Y, Tomonaga M, Koeffler HP. Extensive analysis of the retinoblastoma gene in adult T cell leukemia/lymphoma (ATL). Leukemia. 1997 Jul;11(7):984–989. [PubMed]
  • Howard OM, Shipp MA. The cellular and molecular heterogeneity of the aggressive non-Hodgkin's lymphomas. Curr Opin Oncol. 1998 Sep;10(5):385–391. [PubMed]
  • Korkolopoulou P, Angelopoulou MK, Kontopidou F, Tsenga A, Patsouris E, Thomas-Tsagli E, Kittas C, Pangalis GA. Prognostic relevance of apoptotic cell death in non-Hodgkin's lymphomas: a multivariate survival analysis including Ki67 and p53 oncoprotein expression. Histopathology. 1998 Sep;33(3):240–247. [PubMed]
  • Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992 Sep 24;359(6393):288–294. [PubMed]
  • Leoncini L, Bellan C, Cossu A, Claudio PP, Lazzi S, Cinti C, Cevenini G, Megha T, Laurini L, Luzi P, et al. Retinoblastoma-related p107 and pRb2/p130 proteins in malignant lymphomas: distinct mechanisms of cell growth control. Clin Cancer Res. 1999 Dec;5(12):4065–4072. [PubMed]
  • Mochen C, Giardini R, Costa A, Silvestrini R. MIB-1 and S-phase cell fraction predict survival in non-Hodgkin's lymphomas. Cell Prolif. 1997 Jan;30(1):37–47. [PubMed]
  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9–22. [PubMed]
  • Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR, Roberts JM. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med. 1997 Feb;3(2):222–225. [PubMed]
  • Quintanilla-Martinez L, Thieblemont C, Fend F, Kumar S, Pinyol M, Campo E, Jaffe ES, Raffeld M. Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor. Am J Pathol. 1998 Jul;153(1):175–182. [PubMed]
  • Reynisdóttir I, Polyak K, Iavarone A, Massagué J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 1995 Aug 1;9(15):1831–1845. [PubMed]
  • Rustgi AK, Dyson N, Bernards R. Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product. Nature. 1991 Aug 8;352(6335):541–544. [PubMed]
  • Sherr CJ. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. [PubMed]
  • Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. [PubMed]
  • Stefanaki K, Tzardi M, Kouvidou C, Chaniotis V, Bolioti M, Vlychou M, Zois M, Kakolyris S, Delides G, Rontogianni D, et al. Expression of p53, p21, mdm2, Rb, bax and Ki67 proteins in lymphomas of the mucosa-associated lymphoid (MALT) tissue. Anticancer Res. 1998 Jul-Aug;18(4A):2403–2408. [PubMed]
  • Stranks G, Height SE, Mitchell P, Jadayel D, Yuille MA, De Lord C, Clutterbuck RD, Treleaven JG, Powles RL, Nacheva E, et al. Deletions and rearrangement of CDKN2 in lymphoid malignancy. Blood. 1995 Feb 15;85(4):893–901. [PubMed]
  • Uchida T, Kinoshita T, Murate T, Saito H, Hotta T. CDKN2 (MTS1/p16INK4A) gene alterations in adult T-cell leukemia/lymphoma. Leuk Lymphoma. 1998 Mar;29(1-2):27–35. [PubMed]
  • Vrhovac R, Delmer A, Tang R, Marie JP, Zittoun R, Ajchenbaum-Cymbalista F. Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia. Blood. 1998 Jun 15;91(12):4694–4700. [PubMed]
  • Welch PJ, Wang JY. A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell. 1993 Nov 19;75(4):779–790. [PubMed]
  • Xiao ZX, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR, Livingston DM. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 1995 Jun 22;375(6533):694–698. [PubMed]
  • Yasui W, Kudo Y, Semba S, Yokozaki H, Tahara E. Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is associated with advanced stage and invasiveness of gastric carcinomas. Jpn J Cancer Res. 1997 Jul;88(7):625–629. [PubMed]
  • Zheng T, Mayne ST, Boyle P, Holford TR, Liu WL, Flannery J. Epidemiology of non-Hodgkin lymphoma in Connecticut. 1935-1988. Cancer. 1992 Aug 15;70(4):840–849. [PubMed]
  • Zucca E, Bertoni F, Roggero E, Cavalli F. Management of rare forms of lymphoma. Curr Opin Oncol. 1998 Sep;10(5):377–384. [PubMed]

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