scholarly journals GSK-3b inhibition: At the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma

Cell Cycle ◽  
2008 ◽  
Vol 7 (18) ◽  
pp. 2813-2816 ◽  
Author(s):  
Jessica Dal Col ◽  
Riccardo Dolcetti
Keyword(s):  
Protein Stability ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Constitutive Activation ◽  
Cyclin D1 Protein ◽  
Mantle Cell

scholarly journals Immunohistochemical Analysis of Cyclin D1 Protein in Hematopoietic Neoplasms with Special Reference to Mantle Cell Lymphoma

1994 ◽  
Vol 85 (12) ◽  
pp. 1270-1279 ◽  
Author(s):  
Shigeo Nakamura ◽  
Masao Seto ◽  
Shogo Banno ◽  
Susumu Suzuki ◽  
Takashi Koshikawa ◽  
...  
Keyword(s):  
Special Reference ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Immunohistochemical Analysis ◽  
Cyclin D1 Protein ◽  
Mantle Cell

scholarly journals Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2715-2723 ◽  
Author(s):  
CJ de Boer ◽  
E Schuuring ◽  
E Dreef ◽  
G Peters ◽  
J Bartek ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Formalin Fixed Paraffin ◽  
Cyclin D1 Protein ◽  
Mantle Cell ◽  
Formalin Fixed Paraffin Embedded ◽  
Formalin Fixed

Abstract Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin-embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.

scholarly journals Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2667-2673 ◽  
Author(s):  
Norihiko Kawamata ◽  
John Chen ◽  
H. Phillip Koeffler
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Hydroxamic Acid ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Kinase Assay ◽  
Suberoylanilide Hydroxamic Acid ◽  
Mrna Levels ◽  
Cyclin D1 Protein ◽  
Mantle Cell

Mantle cell lymphoma (MCL) has a chromosomal translocation resulting in the expression of the cyclin D1 gene driven by the powerful enhancer of the immunoglobulin heavy chain gene, leading to uncontrolled, overexpressed cyclin D1 protein. We showed that suberoylanilide hydroxamic acid (SAHA; vorinostat), one of the histone deacetylase inhibitors derived from hydroxamic acid, caused a dramatic decrease (90%) in protein levels of cyclin D1 after 8-hour exposure to SAHA (5 μM) in MCL lines (SP49, SP53, Jeko1). mRNA levels and protein stability of cyclin D1 were minimally affected by SAHA over 8 hours. In contrast, metabolic labeling assays showed that SAHA decreased incorporation of [35S]methionine into cyclin D1 protein. The drug also decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR), and eukaryotic translation initiation factor 4E binding protein (eIF4E-BP) and lowered the cap site binding activity of eIF4E in the MCL cells. In vitro phosphatidyl inositol (PI) kinase assay demonstrated that SAHA directly inhibited kinase activity of PI 3′ kinase. Taken together, SAHA caused a rapid decrease of cyclin D1 in MCL by blocking the translation of cyclin D1 by inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR/eIF4E-BP pathway, probably by PI3K inhibition.

scholarly journals Cyclin D1 protein expression in mantle cell lymphoma

1995 ◽  
Vol 6 (6) ◽  
pp. 567-570 ◽  
Author(s):  
S. Alkan ◽  
B. Schnitzer ◽  
J.L. Thompson ◽  
L.C. Moscinski ◽  
C.W. Ross
Keyword(s):  
Protein Expression ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Cyclin D1 Protein ◽  
Mantle Cell

bcl-1 REARRANGEMENT AND CYCLIN D1 PROTEIN EXPRESSION IN MANTLE CELL LYMPHOMA

1996 ◽  
Vol 179 (3) ◽  
pp. 238-242 ◽  
Author(s):  
M. MICHAELA OTT ◽  
ANITA HELBING ◽  
GERMAN OTT ◽  
JIRI BARTEK ◽  
LARS FISCHER ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Cyclin D1 Protein ◽  
Mantle Cell

scholarly journals Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2715-2723 ◽  
Author(s):  
CJ de Boer ◽  
E Schuuring ◽  
E Dreef ◽  
G Peters ◽  
J Bartek ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Formalin Fixed Paraffin ◽  
Cyclin D1 Protein ◽  
Mantle Cell ◽  
Formalin Fixed Paraffin Embedded ◽  
Formalin Fixed

Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin-embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.

Mantle Cell Lymphoma: SAHA Blocks Akt/mTOR Pathway and Reduces Cyclin D1 Protein Levels by Affecting Translation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3293-3293 ◽  
Author(s):  
Norihiko Kawamata ◽  
H. Phillip Koeffler
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Binding Activity ◽  
Mtor Pathway ◽  
Protein Levels ◽  
Cyclin D1 Protein ◽  
Mantle Cell

Abstract Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor. We have found that SAHA has profound antiproliferative activities against mantle cell lymphoma (MCL) cell lines (ED50 ≅ 1 μM SAHA for 3 days), and this was associated with a rapid decrease of Cyclin D1 protein as seen by western blot. For example, eight hours treatment with SAHA (5 μM), reduced the Cyclin D1 levels by 80 % in three of 3 MCL cell lines (Jeko1, SP49, SP53). In contrast, other HDAC inhibitors including valproic acid and trichostatin A, were unable to reduce protein levels of Cyclin D1 as rapidly or as completely as SAHA in these MCL cell lines. Also, a myelogenous leukemia cell line, K562 expressed low levels of Cyclin D1 and exposure of these cells to SAHA (8 hrs) had almost no effect on protein levels of Cyclin D1, although SAHA had profound antiproliferative effect on these cells. A hallmark of MCL cells is the t(11; 14)(q13; q32) chromosomal change which rearranges the enhancer region of the immunoglobulin heavy chain to the regulatory region of the cyclin D1 gene inducing overexpression of Cyclin D1 mRNA, leading to high expression of Cyclin D1 protein. Levels of Cyclin D1 mRNA (Northern blot) remained elevated in these cell lines during an 8 hr exposure to SAHA (5 μM). Also, stability of Cyclin D1 protein in these MCL lines as measured by pulse-chase assay and cyclohexamide treatment minimally changed during the 8 hours of exposure to SAHA in the MCL cell lines. Taken together, we speculated that translation of the Cyclin D1 may be slowed after treatment of the cells with SAHA. Since translation of Cyclin D1 protein is regulated by eIF4E, the binding activity of eIF4E to the cap site of mRNA was analyzed by immunoprecipitation using 7 methyl-GTP sepharose beads. Binding activity decreased rapidly after the treatment with SAHA. Since hypophosphorylated eIF4EBP binds eIF4E and blocks the function of eIF4E, activity of eIF4E is regulated by eIF4EBP and its phosphorylation status. Furthermore, Akt phosphorylates and activates mTOR which then phosphorylates eIF4EBP and prevents eIF4EBP from binding to eIF4E. We found that eIF4EBP, mTOR, and Akt proteins are markedly phosphorylated resulting in an activated Akt/mTOR pathway in the MCL cell lines. Levels of phospho-eIF4EBP, phosph-mTOR and phospho-Akt decreased rapidly after treatment with SAHA. Also, PI3K inhibitor, LY294002, transiently decreased the level of Cyclin D1 protein. In summary, our data suggest that 1) Akt/mTOR pathway is activated in MCL cells; 2) Translation of Cyclin D1 is dependent on this pathway in these cells; 3) Blockade of this pathway reduces the protein levels of Cyclin D1 rapidly by decreasing its translation; 4) SAHA blocks this pathway through a mechanism other than HDAC inhibition. This discovery may encourage a reappraisal of the mechanism of action of this interesting therapeutic compound and also focus attention to developing additional inhibitors of this pathway in cancers associated with dysregulated Cyclin D1.

Complex analysis of cyclin D1 expression in mantle cell lymphoma: two cyclin D1-negative cases detected

2009 ◽  
Vol 62 (10) ◽  
pp. 948-950 ◽  
Author(s):  
L Stefancikova ◽  
M Moulis ◽  
P Fabian ◽  
I Falkova ◽  
I Vasova ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Complex Analysis ◽  
Cell Lymphoma ◽  
In Situ Hybridisation ◽  
D1 Protein ◽  
Fluorescence In Situ Hybridisation ◽  
Cyclin D2 ◽  
Mantle Cell ◽  
High Level

Background and Aim:The cytogenetic and diagnostic hallmark of mantle cell lymphoma (MCL) is translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1. Cyclin D1 expression was analysed in 32 cases of MCL.Methods:The t(11;14) translocation was detected by fluorescence in situ hybridisation, level of cyclin D1 mRNA by competitive RT-PCR, and level of cyclin D1 and D2 proteins by immunohistochemistry and/or immunoblotting.Results:In 30 cases, the presence of translocation t(11;14), a high level of cyclin D1 mRNA, and a high level of the cyclin D1 protein were confirmed. Two cyclin D1-negative cases overexpressing cyclin D2 were detected by immunoblotting.Conclusions:There are rare cyclin D1-negative cases of MCL overexpressing cyclin D2. Anti-cyclin D1 antibodies with low specificity can bind both cyclin D1 and cyclin D2, thus providing false cyclin D1-positive signals in immunohistochemical analysis.

A Unique Case of Mantle Cell Lymphoma With an Aberrant CD5−/CD10+ Immunophenotype and Typical Morphology

2008 ◽  
Vol 132 (8) ◽  
pp. 1346-1349
Author(s):  
Vathany Sriganeshan ◽  
Thomas R. Blom ◽  
David J. Weissmann
Keyword(s):  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
D1 Protein ◽  
Small Lymphocytic Lymphoma ◽  
Unique Case ◽  
Non Hodgkin Lymphoma ◽  
Cyclin D1 Protein ◽  
Mantle Cell ◽  
Typical Morphology

Abstract Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with a poor prognosis that may be confused with less aggressive diseases, such as small lymphocytic lymphoma and follicular lymphoma. In many cases immunophenotyping, particularly analysis of reactivity for CD5 and CD10, is an important adjunct to morphology that usually distinguishes MCL from follicular lymphoma; the former is CD5+/CD10−, whereas follicular lymphoma is the reverse. We report a case of MCL, initially diagnosed as follicular lymphoma, that at presentation expressed neither CD5 nor CD10. At relapse, it was still CD5−, but CD10 was now detected. Studies for a t(11;14) translocation and CYCLIN D1 protein expression, however, permitted a revised diagnosis of MCL. An MCL with this immunophenotype and classical morphology has not been previously reported.

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