Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p70S6K/p85S6K and cdc2/cdk1 are members of the serine/threonine protein kinase family. p70S6K/p85S6K is one of the downstream effectors of the PI3K/Akt/mTOR signal transduction pathway. It phosphorylates S6 protein of 40S ribosomal subunit and thus functions in protein synthesis and cell growth. cdc2/cdk1 is a cyclin-dependent protein kinase that controls the cell cycle entry from G2 to M phase. Overexpression of phospho-p70S6K and cdc2/cdk1 has recently been identified in the majority of diffuse large B-cell lymphoma (DLBCL) specimens. Combination of small molecules that target phosphorylation of p70S6K and cdc2/cdk1 synergistically induced cell apoptosis and cell cycle G1 and G2 arrest, suggesting that they are potential molecular targets for DLBCL therapy. This review will summarize recent advances in the study of phospho-p70S6K and cdc2/cdk1 as molecular markers and therapeutic targets for DLBCL. We propose that multilevel inhibition of the PI3K/Akt/mTOR pathway and double brake at the G1 and G2 phases of the cell cycle progression are effective strategies in treating DLBCL that overexpress phospho-p70S6K and cdc2/cdk1.
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PMID:Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma. 1961 61

The Epstein-Barr virus (EBV)-encoded RNAs, EBER-1 and EBER-2, are highly abundant noncoding nuclear RNAs expressed during all forms of EBV latency. The EBERs have been shown to impart significant tumorigenic potential upon EBV-negative Burkitt lymphoma (BL) cells and to contribute to the growth potential of other B-cell lymphoma-, gastric carcinoma-, and nasopharyngeal carcinoma-derived cell lines. However, the mechanisms underlying this EBER-dependent enhancement of cell growth potential remain to be elucidated. Here we focused on the known interaction between EBER-1 and the cellular ribosomal protein L22 and the consequences of this interaction with respect to the growth-promoting properties of the EBERs. L22, a component of 60S ribosomal subunits, binds three sites on EBER-1, and a substantial fraction of available L22 is relocalized from nucleoli to the nucleoplasm in EBV-infected cells. To investigate the hypothesis that EBER-1-mediated relocalization of L22 in EBV-infected cells is critical for EBER-dependent functions, we investigated whether EBER-1 expression is necessary and sufficient for nucleoplasmic retention of L22. Following demonstration of this, we utilized RNA-protein binding assays and fluorescence localization studies to demonstrate that mutation of the L22 binding sites on EBER-1 prevents L22 binding and inhibits EBER-1-dependent L22 relocalization. Finally, the in vivo consequence of preventing L22 relocalization in EBER-expressing cells was examined in soft agar colony formation assays. We demonstrate that BL cells expressing mutated EBER-1 RNAs rendered incapable of binding L22 have significantly reduced capacity to enhance cell growth potential relative to BL cells expressing wild-type EBERs.
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PMID:Growth-promoting properties of Epstein-Barr virus EBER-1 RNA correlate with ribosomal protein L22 binding. 1964 Sep 98

p27(BBP)/eIF6 (beta4-binding protein/eukaryotic initiation factor 6) regulates the joining of 40S and 60S ribosomal subunits, on receptor for activated C kinase 1 binding and protein kinase C phosphorylation in serine 235. In Xenopus, p27(BBP)/eIF6 is abundantly expressed in the majority of the embryonic anlagen. Although p27(BBP)/eIF6 abundance may be required for a general regulation of protein synthesis, our data suggest that p27(BBP)/eIF6 may target the translation of specific mRNAs. We injected Xp27(BBP)/eIF6 mRNA in one blastomere of two-cell-stage embryos and obtained a bent phenotype, the curvature being lateral with respect to the embryo antero-posterior axis. The injected side had fewer apoptotic cells than the uninjected side, whereas cell proliferation appeared unaffected. Accordingly, in Xp27(BBP)/eIF6 morphants, endogenous apoptosis increased. Injection of Xp27(BBP)/eIF6 point mutants indicated that the anti-apoptotic action of Xp27(BBP)/eIF6 requires the conserved S235. The bent phenotype was also obtained with B-cell lymphoma gene-2 (Bcl-2) overexpression and was rescued by Bcl-2-associated X protein (Bax)/Xp27(BBP)/eIF6 co-injection. In addition, embryos overexpressing Xp27(BBP)/eIF6 had a higher amount of Bcl-2 and an unchanged amount of Bax with respect to controls. In Xp27(BBP)/eIF6 morphants, Bcl-2 levels were unaffected and Bax levels were higher than in the controls. Thus, we propose that Xp27(BBP)/eIF6 is part of a mechanism acting on the specific translation of messengers regulating cell survival. In particular, we suggest that Xp27(BBP)/eIF6 may regulate the translation of factors upstream of Bcl-2/Bax.
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PMID:p27(BBP)/eIF6 acts as an anti-apoptotic factor upstream of Bcl-2 during Xenopus laevis development. 1977 96

The molecular mechanism(s) linking tumorigenesis and morphological alterations in the nucleolus are presently coming into focus. The nucleolus is the cellular organelle in which the formation of ribosomal subunits occurs. Ribosomal biogenesis occurs through the transcription of ribosomal RNA (rRNA), rRNA processing and production of ribosomal proteins. An error in any of these processes may lead to deregulated cellular translation, evident in multiple cancers and 'ribosomopathies'. Deregulated protein synthesis may be achieved through the overexpression of ribosomal proteins as seen in primary leukemic blasts with elevated levels of ribosomal proteins S11 and S14. In this study, we demonstrate that ribosomal protein S6 (RPS6) is highly expressed in primary diffuse large B-cell lymphoma (DLBCL) samples. Genetic modulation of RPS6 protein levels with specifically targeted short hairpin RNA (shRNA) lentiviruses led to a decrease in the actively proliferating population of cells compared with control shRNA. Low-dose rapamycin treatments have been shown to affect the translation of 5' terminal oligopyrimidine (5' TOP) tract mRNA, which encodes the translational machinery, implicating RPS6 in 5' TOP translation. Recently, it was shown that disruption of 40S ribosomal biogenesis through specific small inhibitory RNA knockdown of RPS6 defined RPS6 as a critical regulator of 5' TOP translation. For the first time, we show that RPS6 associates with multiple mRNAs containing a 5' TOP tract. These findings expand our understanding of the mechanism(s) involved in ribosomal biogenesis and deregulated protein synthesis in DLBCL.
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PMID:Ribosomal protein S6 is highly expressed in non-Hodgkin lymphoma and associates with mRNA containing a 5' terminal oligopyrimidine tract. 2110 26