cyclin-d1 and Thymoma

Lysosome-associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2) are implicated in a variety of normal and pathological processes. LAMP-2 is proposed to participate in chaperone-mediated autophagy.Autophagy regulates T-lymphocyte homeostasis by promoting both survival and proliferation. The biological importance of this process in the thymic gland and especially the involvement of LAMPs are far from being elucidated. The aim of the study was to examine the parallel expression of LAMPs and ubiquitin, a key molecule in autophagy, in normal human thymic glands and thymomas. The immunohistochemical expression of both markers was compared with that of cyclin D1--an important regulator of cell cycle progression. Novel evidence for differential expression of LAMPs and ubiquitin is presented. Most Hassal's corpuscules in thymoma were negative for LAMPs, but positive in normal thymus.Both lymphocytes and epithelial cells in pathological thymus showed higher intensity for LAMP-2 compared with LAMP-1. In thymoma, ubiquitin was more intensively positive in these cell types compared with the normal thymus, suggesting activated autophagy in the course of this pathological state. A deregulation in cyclin D1 expression in thymoma is also reported. The functional importance of these molecules in autophagy accompanying normal and pathological processes in the thymic gland is reviewed.

Topics: Child; Child, Preschool; Cyclin D1; Humans; Immunohistochemistry; Infant; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Thymoma; Thymus Gland; Thymus Neoplasms; Ubiquitin

Mounting evidence implicates deregulated Rel/NF-kappaB signaling as a common feature of lymphoid malignancies. Despite the fact that they promote the survival and proliferation of normal lymphocytes, the underlying mechanisms by which various Rel/NF-kappaB proteins with different transcriptional regulatory capacities might facilitate transformation remain to be established. Here we show that the proliferation and tumorigenicity of Abelson murine leukemia virus (A-MuLV)-transformed pre-B cells are enhanced in the absence of NF-kappaB1 and that this coincides with elevated levels of cyclin D1. Support for a link between cyclin D1 expression and v-Abl transformation came from the finding that proliferation of transformed pre-B cells was reduced in the absence of cyclin D1, while enforced cyclin D1 expression increased the proliferation and tumorigenicity of wild-type transformants. A reduction in endogenous cyclin D1 levels that coincided with NF-kappaB1 transgene reversal of enhanced nfkb1(-/-) pre-B-cell transformation, coupled with NF-kappaB1 inhibition of v-Abl-induced kappaB-dependent murine cyclin D1 transcription, lends support to a model in which v-Abl-induced cyclin D1 transcription in transformed pre-B cells is controlled by Rel/NF-kappaB dimers with different activities.

Topics: Abelson murine leukemia virus; Animals; B-Lymphocytes; Bone Marrow Cells; Bone Marrow Transplantation; Cell Transformation, Neoplastic; Cyclin D1; Dimerization; G1 Phase; Gene Expression Regulation, Neoplastic; Genes, abl; Leukemia, Experimental; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Protein Subunits; Proto-Oncogene Proteins c-rel; Stem Cells; Survival Rate; Thymoma

There have been few reports on genetic alterations in thymomas. To investigate the expression of p16INK4A, RB, p53 and cyclin D1 in thymomas, we first examined 36 thymomas (non-invasive type, 16 cases; invasive type, 20 cases) and 3 thymic carcinomas, using immunohistochemistry. Abnormal expression of p16INK4A, RB, p53 and cyclin D1 was observed in 18, 8, 10 and 7 cases, respectively. Only a subgroup of invasive thymomas and thymic carcinomas showed an inverse correlation between p16INK4A and RB expression. Subsequently, we examined the 36 thymomas and 4 thymic carcinomas for mutations in p53 and CDKN2 genes, using PCR-SSCP and direct-sequencing analyses. No mutation of these genes was detected in the thymomas and thymic carcinomas examined. A polymorphism in the 3' untranslated region of exon 3 of CDKN2 was detected in 5 cases of thymoma. We searched for hypermethylation in the promoter region of CDKN2, observing it in 4 thymomas and 1 thymic carcinoma. Our data suggest that, unlike other more common cancers, alteration of the p53 gene may not play a significant role in the tumorigenesis of thymoma. However, inactivation of p16INK4A and RB may play a role in the progression of thymoma and thymic carcinoma.

Topics: Blotting, Southern; Carcinoma; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; DNA Mutational Analysis; DNA Primers; DNA-Binding Proteins; DNA, Neoplasm; Genes, p16; Genes, p53; Humans; Immunohistochemistry; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Retinoblastoma Protein; Thymoma; Thymus Neoplasms; Tumor Suppressor Protein p53