Cap-mediated messenger RNA translation controlled by the eukaryotic initiation factor 4F (eIF-4F) complex plays a key role in human cancer. eIF-4F activity is controlled by a repressor binding protein (4E-BP1), which promotes translation when phosphorylated.
To examine the level of expression and phosphorylation of 4E-BP1 in various subtypes of B-cell lymphoma and reactive lymphoid tissues.
Archival formalin-fixed, paraffin-embedded B-cell lymphoma samples and reactive lymphoid tissues were immunostained and examined for expression of 4E-BP1 and phosphorylated 4E-BP1. Expression of components of the eIF-4F complex and unphosphorylated and phosphorylated 4E-BP1 was confirmed using Western immunoblotting on lysates of frozen lymphoma samples and reactive tissues.
Immunohistochemical analysis demonstrated weak to undetectable 4E-BP1 staining within benign, reactive germinal centers (N = 10). In contrast, 4E-BP1 was consistently expressed (moderate to strong staining) in 98% of various subtypes of mature B-cell lymphoma (N = 50). 4E-BP1 expression was also demonstrable in all 4 lymph nodes with in situ or partial involvement by follicular lymphoma and in all 12 cases of BCL2-negative lymphoma. The level of phosphorylation of 4E-BP1 in lymphomas, evaluated by immunohistochemistry, was heterogeneous.
The immunohistochemical expression pattern of 4E-BP1 exhibits regional and cellular specificity in reactive lymphoid tissues and may offer a diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations.
"The present study shows that nicotinamide promotes C17.2 NSCs apoptosis and decreases bcl-2 expression, illustrating bcl-2 involves nicotinamide-induced apoptosis in c17.2NSCs. 4EBP1 is a member of translation repressor proteins family, and phosphorylation of 4EBP1 induces activation of mRNA translation (Kodali et al. 2011). However, this study shows that nicotinamide down-regulates phosphorylation of 4EBP1 in C17.2 NSCs. "
[Show abstract][Hide abstract] ABSTRACT: Histone deacetylase inhibitors are involved in proliferation, apoptosis, cell cycle, mRNA transcription, and protein expression in various cells. However, the molecular mechanism underlying such functions is still not fully clear. In this study, we used C17.2 neural stem cell (NSC) line as a model to evaluate the effects of nicotinamide and trichostatin A (TSA) on cell characteristics. Results show that nicotinamide and TSA greatly inhibit cell growth, lead to cell morphology changes, and effectively induce cell apoptosis in a dose-dependent manner. Western blot analyses confirmed that nicotinamide significantly decreases the expression of bcl-2 and p38. Further insight into the molecular mechanisms shows the suppression of phosphorylation in eukaryotic initiation factor 4E-binding protein 1 (4EBP1) by nicotinamide, whereas, an increased expression of bcl-2 and p38 and phosphorylation of 4EBP1 by TSA. However, both nicotinamide and TSA significantly increase the expression of cytochrome c (cyt c). These results strongly suggest that bcl-2, p38, cyt c, and p-4EBP1 could suppress proliferation and induce apoptosis of C17.2 NSCs mediated by histone deacetylase inhibitors, nicotinamide and TSA, involving different molecular mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Protein translation initiation is controlled by eukaryotic initiation factor 4E (eIF-4E) binding protein 1 (4E-BP1). Phosphorylated 4E-BP1 dissociates from eIF-4E, allowing translation of transcripts mediating cell cycling, survival, and angiogenesis. The expression and phosphorylation of 4E-BP1, and influence on prognosis of diffuse large B cell lymphoma (DLBCL), is unknown. Because at least some patients with low-risk (International Prognostic Index score 0–2) DLBCL treated with standard anthracycline-based chemotherapy experience a short survival, we examined if 4E-BP1 expression and phosphorylation may provide additional prognostic information in 35 patients with low-risk DLBCL. We examined their initial diagnostic pathology specimens for 4E-BP1 expression and phosphorylation using immunohistochemistry, and we correlated these with clinical outcomes. While 4E-BP1 was uniformly expressed, there was wide distribution in its level of phosphorylation (biological activity). 4E-BP1 phosphorylation correlated strongly with overall survival (OS; P = 0.007) and progression-free survival (PFS; P = 0.02) and was the most significant independent variable for both OS and PFS on multivariable analysis. Our findings suggest that immunohistochemical evaluation of 4E-BP1 phosphorylation may help refine the prognostication of patients with low-risk DLBCL. Prospective studies in an independent cohort of patients are warranted.
Helene Kretzmer, Stephan H Bernhart, Wei Wang, Andrea Haake, Marc A Weniger, Anke K Bergmann, Matthew J Betts, Enrique Carrillo-de-Santa-Pau, Gero Doose, Jana Gutwein, [...], Peter F Stadler, Monika Szczepanowski, Lorenz Trümper, Hendrik G Stunnenberg, Ralf Küppers, Ole Ammerpohl, Peter Lichter, Reiner Siebert, Steve Hoffmann, Bernhard Radlwimmer
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