Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD44 is a transmembrane glycoprotein occurring in several isoforms with different extracellular regions. The various transcripts are encoded by one gene locus containing 20 exons, of which at least 10 can be alternatively spliced in nascent RNA. Isoforms encoded by the variant exons (termed CD44v) are highly restricted in their distribution in nonmalignant tissue as opposed to the standard form of CD44 (CD44s) abundant in many tissues. Specific variant isoforms containing exon 6v have been shown to render nonmetastatic rat tumor cells metastatic. Based on the prominent role in rat metastasis formation, CD44v isoforms were suggested to be involved in human tumor progression. Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma. We evaluated the expression of CD44 isoforms in node-positive (n = 119) and node-negative (n = 108) cases of breast carcinoma by immunohistochemistry using CD44v exon-specific mAbs. In a subset of 43 cases of high-risk patients, reverse transcription-PCR was used to determine the exon composition of the transcripts. Protein and RNA expression data were probed statistically for their correlation to survival of the patients and clinical risk factors. In contrast to recently published data (M. Kaufmann et al., Lancet, 345: 615-619, 1995), in our cohort disease-free and overall survival data did not indicate significant correlations with the expression of the analyzed isoforms in univariate and multivariate analyses. Comparison of CD44 protein expression with established clinical risk factors for survival such as tumor size (pT1+pT2) and histological grading revealed correlations with the presence of CD44s (P = 0.02 and P = 0.03, respectively) and CD44-9v (P = 0.05 for histological grading). Carcinoma tissues with elevated estrogen and progesterone receptor levels showed positive correlation with CD44-6v (P = 0.001), while a trend for significant coexpression of CD44s and CD44-9v isoforms was observed in estrogen receptor-positive tissues (P = 0.08 and 0.06, respectively). In breast cancer, CD44s, CD44-9v, and CD44-6v are apparently markers for cellular differentiation but not for tumor progression. Our data suggest that steroid hormone receptors may be associated with the in vivo expression of CD44-6v-containing isoforms in human mammary carcinoma.
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PMID:CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. 758 12

The presence of soluble differentiation antigens has been recently shown in the sera of healthy subjects and in different pathological disorders. These soluble antigens represent truncated froms of membrane receptors that lack transmembrane and intracytoplasmic domains. They may rise from proteolytic cleavage of the original membrane-bound receptor or by synthesis from separate alternatively spliced mRNA's coding for soluble forms. Increased levels of soluble IL-2R, sCD8 were found in adult T cell leukemia, hairy cell leukemia Hodgkin's disease, non-Hodgkin's lymphoma and chronic lymphocytic leukemia. The presence of sCD30 was found in the above mentioned diseases except for hairy cell leukemia. Serum levels of sIL-2R, sCD8, sCD30 antigens correlated strictly with disease activity and results of treatment.
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PMID:[Circulating cell differentiation antigens as markers of activity in lymphoproliferative diseases]. 806 7

The clinical application of rituximab (chimeric mouse anti-human CD20 mAb, Rituxan, IDEC-C2B8), alone and/or combined with chemotherapy, has significantly ameliorated the treatment outcome of patients with relapsed and refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). The exact in vivo mechanisms of action of rituximab are not fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis have been suggested. We have proposed that modifications of the cellular signaling pathways by rituximab may be crucial for its clinical response. The B-cell restricted cell surface phosphoprotein CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon crosslinking. Monomeric rituximab chemosensitizes drug-resistant NHL cells via selective downregulation of antiapoptotic factors through the type II mitochondrial apoptotic pathway. Several signaling pathways are affected by rituximab which are implicated in the underlying molecular mechanisms of chemosensitization. ARL (acquired immunodeficiency syndrome (AIDS)-related lymphoma) and non-ARL cell lines have been examined as in vitro model systems. In ARL, rituximab diminishes the activity of the p38MAPK signaling pathway resulting in inhibition of the interleukin (IL)-10/IL-10R autocrine/paracrine cytokine autoregulatory loop leading to the inhibition of constitutive STAT-3 activity and subsequent downregulation of Bcl-2 expression leading to chemosensitization. Rituximab upregulates Raf-1 kinase inhibitor protein (RKIP) expression in non-ARL cells. Through physical association with Raf-1 and nuclear factor kappaB (NF-kappa B)-inducing kinase (NIK), RKIP negatively regulates two major survival pathways, namely, the extracellular signal-regulated kinase1/2 (ERK1/2) and the NF-kappa B pathways, respectively. Downmodulation of the ERK1/2 and NF-kappa B pathways inhibits the transcriptional activity of AP-1 and NF-kappa B transcription factors, respectively, both of which lead to the downregulation of Bcl-(xL) (Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)) transcription and expression and sensitization to drug-induced apoptosis. Bcl-(xL)-overexpressing cells corroborated the pivotal role of Bcl-(xL) in chemosensitization. The specificity of rituximab-mediated signaling and functional effects were corroborated by the use of specific pharmacological inhibitors. Many patients do not respond and/or relapse and the mechanisms of unresponsiveness are unknown. Rituximab-resistant B-NHL clones were generated to investigate the acquired resistance to rituximab-mediated signaling, and chemosensitization. Resistant clones display different phenotypic, genetic and functional properties compared to wild-type cells. This review summarizes the data highlighting a novel role of rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Studies presented herein also reveal several intracellular targets modified by rituximab, which can be exploited for therapeutic and prognostic purposes in the treatment of patients with rituximab- and drug-refractory NHL.
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PMID:Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. 1578 36

Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi's sarcoma, non-Hodgkin's lymphoma, and cervical cancer. This aberrant splicing leads to abnormal production of protein and is caused by mutations in cis-acting elements or trans-acting factors in angiogenesis-related genes. Restoring the normal regulation of alternative splicing of angiogenic genes would alter the expression of protein isoforms and may confer normal cell physiology in patients with these cancers. This review highlights the abnormalities in alternative splicing of angiogenesis-related genes and their implication in HIV/AIDS-related cancers. This allows us to gain an insight into the pathogenesis of HIV/AIDS-related cancer and in turn elucidate the therapeutic potential of alternatively spliced genes in HIV/AIDS-related malignancies.
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PMID:Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers. 2869 6