25
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          The CCND1 gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of a common A/G polymorphism. Cyclin D1a and b proteins differ in their C-terminus, a region involved in protein degradation and sub-cellular localization. Recent data have suggested that cyclin D1b could be a nuclear oncogene. The presence of cyclin D1b mRNA and protein has been studied in two hemopathies in which cyclin D1 could be present: multiple myeloma (MM) and mantle cell lymphoma (MCL). The A/G polymorphism of CCND1 has also been verified in a series of patients.

          Methods

          The expression of cyclin D1 mRNA isoforms has been studied by real-time quantitative PCR; protein isoforms expression, localization and degradation by western blotting. The CCND1 polymorphism was analyzed after sequencing genomic DNA.

          Results

          Cyclin D1 mRNA isoforms a and b were expressed in mantle cell lymphoma (MCL) and multiple myeloma (MM). Cyclin D1b proteins were present in MCL, rarely in MM. Importantly, both protein isoforms localized the nuclear and cytoplasmic compartments. They displayed the same short half-life. Thus, the two properties of cyclin D1b recognized as necessary for its transforming activity are missing in MCL. Moreover, CCND1 polymorphism at the exon/intron boundary had no influence on splicing regulation in MCL cells.

          Conclusion

          Our results support the notion that cyclin D1b is not crucial for the pathogenesis of MCL and MM.

          Related collections

          Most cited references16

          • Record: found
          • Abstract: found
          • Article: not found

          Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma.

          Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiploid pathway associated with a high prevalence of IgH translocations and a hyperdiploid pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40% of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1+D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma.

            We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage.

              DNA damage causes stabilization of p53, leading to G1 arrest through induction of p21cip1. As this process requires transcription, several hours are needed to exert this response. We show that DNA damage causes an immediate and p53-independent G1 arrest, caused by rapid proteolysis of cyclin D1. Degradation is mediated through a previously unrecognized destruction box in cyclin D1 and leads to a release of p21cip1 from CDK4 to inhibit CDK2. Interference with cyclin D1 degradation prevents initiation of G1 arrest and renders cells more susceptible to DNA damage, indicating that cyclin D1 degradation is an essential component of the cellular response to genotoxic stress. Thus, induction of G1 arrest in response to DNA damage is minimally a two step process: a fast p53-independent initiation of G1 arrest mediated by cyclin D1 proteolysis and a slower maintenance of arrest resulting from increased p53 stability.
                Bookmark

                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                2006
                6 October 2006
                : 6
                : 238
                Affiliations
                [1 ]Laboratoire de Biologie Moléculaire et Cellulaire de la Signalisation, EA 3919, Université de Caen, France
                [2 ]Laboratoire d'Hématologie, CHU Côte de Nacre, Caen, France
                Article
                1471-2407-6-238
                10.1186/1471-2407-6-238
                1609182
                17022831
                a19d2708-e1f4-4fee-891b-daeaa7853e24
                Copyright © 2006 Krieger et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 April 2006
                : 6 October 2006
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

                Comments

                Comment on this article