Regulation of ribosomal RNA synthesis in T cells: requirement for GTP and Ebp1

Nguyen, Le Xuan Truong; Lee, Yunqin; Urbani, Lenore J.; Utz, Paul J.; Hamburger, Anne W.; Sunwoo, John B.; Mitchell, Beverly S.

doi:10.1182/blood-2014-12-616433

Cited by 34 publications

(48 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the p48 isoform of Ebp1 has been localized to the nucleolus and shown to bind to RNA, it had not previously been known to participate in the increasingly complex process of regulating rRNA synthesis. We have recently shown that Ebp1 p48 binds to TIF-IA to regulate its intracellular localization and activity (12). Our present studies demonstrate that Ebp1 is also involved in the formation of the rRNA transcription initiation complex, contributing to its ability to regulate rRNA synthesis.…”

Section: Introductionmentioning

confidence: 50%

Expression and Role of the ErbB3-Binding Protein 1 in Acute Myelogenous Leukemic Cells

Nguyen

Zhu

Lee

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: The ErbB3-binding protein 1 (Ebp1) has been implicated in diverse cancers as having either oncogenic or tumor suppressor activities. The present study was undertaken to determine the effects of Ebp1 expression in AML cells and to determine the mechanisms by which Ebp1 promotes cell proliferation in these cells.Experimental Design: The expression of Ebp1 was studied in mononuclear cells obtained from the peripheral blood of 54 patients with AML by Western blot analysis. The effects of Ebp1 expression on proliferating cell nuclear antigen (PCNA) expression and cell proliferation was measured using Western blot analysis, immunoprecipitation, in vitro ubiquitination, and colony-forming assays. The role of Ebp1 in promoting rRNA synthesis and cell proliferation was evaluated by measuring the level of pre-rRNA and the recruitment of Pol I to rDNA.Results: Ebp1 is highly expressed in acute myelogenous leukemia (AML) cells and regulates the level of ribosomal RNA (rRNA) synthesis by binding to RNA Polymerase I (Pol I) and enhancing the formation of the Pol I initiation complex. Ebp1 also increases the stability of PCNA protein by preventing its interaction with Mdm2, for which it is a substrate.Conclusions: These results demonstrate an important role of Ebp1 in promoting cell proliferation in AML cells through the regulation of both rRNA synthesis and PCNA expression. Clin Cancer Res; 22(13); 3320-7. Ó2016 AACR.

show abstract

Section: Introductionmentioning

confidence: 50%

Expression and Role of the ErbB3-Binding Protein 1 in Acute Myelogenous Leukemic Cells

Nguyen

Zhu

Lee

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…While p42 might act as an ErbB3 effector, since its function is associated with ErbB3 expression in breast cells, prostate cells and lung cancer cells, p48 appears to act independently of ErbB3 to promote cancer progression. Besides of cancer cells, in T cells, only p48 protein but not p42 protein expression is detectable and p48 interacts with transcription initiation factor (TIF)−1A, facilitating rRNA synthesis and proliferation along with enhanced transcription of proliferating cell nuclear antigen in T cells, representing growth promoting activity of p48 . Future studies will aim to identify the role of ErbB3 in the regulation and functions of p42 and p48 and to study the roles of other EGFR family members.…”

Section: Discussionmentioning

confidence: 99%

Opposing roles of the two isoforms of ErbB3 binding protein 1 in human cancer cells

Chang

Park

et al. 2016

Intl Journal of Cancer

View full text Add to dashboard Cite

The different functions of the two isoforms of ErbB3 binding protein 1 (Ebp1), p48 and p42, have recently become the focus of interest as they reveal contradictory roles in cell growth promoting ability. The conformational change that crystal structure of p42 was shown to lack a helices at the amino-terminus present in p48 represents the differential binding partners and protein modifications of two Ebp1 isoforms. N-terminal specific phosphorylation by CDK2 and deregulation of the p53 tumor suppressor through specific interaction with HDM2 and Akt activation is postulated to contribute to p48-mediated tumorigenesis. The short isoform p42 Ebp1, which is actual binding partner of ErbB3 has been implicated as a tumor suppressor with many binding partners such as Rb, HDAC2, Sin3A and the p85 subunit of PI3K with HSP70/CHIP, inhibiting its own antiproliferative activity or inhibiting PI3K activity. The aim of the current review is to provide a summary on distinctive cellular functions of two Ebp1 proteins and their molecular partners that might be responsible for the unique functions of each isoform of Ebp1.ErbB3 binding protein 1 (Ebp1) was originally identified as an ErbB3 receptor-binding protein 1 and is the human homolog of mouse p38-2G4, which has been shown to be cell cycle-regulated. 2 Although Ebp1 was originally identified via its interaction with ErbB3, 1 Ebp1 is ubiquitously expressed in all tissues and cells, including cells that do not express the ErbB3 receptor. 3 Ebp1 is evolutionarily conserved, 2,4 suggesting that it may function as a general signaling molecule. PA2G4 encodes two alternatively spliced Ebp1 isoforms, p48 and p42, that are transcribed into two mRNA transcripts; interestingly, however, PA2G4 harbors three in-frame ATG codons. 5 Translation is initiated at the first ATG codon for p48, which migrates at an apparent molecular weight of 48 kDa and is 54 amino acids longer than p42 at the Nterminus. p42 translation begins at the third ATG codon, resulting in the omission of a 29 nucleotide exon, which eliminates the second ATG in the p48 mRNA. The resultant protein migrates at an apparent molecular weight of 42 kDa by SDS/PAGE. 5 The longer form, p48, localizes in both the cytoplasm and the nucleolus and suppresses apoptosis, whereas the shorter form, p42, resides predominantly in the cytoplasm and promotes cell differentiation. 5 Ebp1 binds ribosomes and dsRNA and is also a component of cytoplasmic bcl-2 messenger ribonucleoprotein (mRNP). 6,7 Recently, we showed that p48 Ebp1 associates with nuclear Akt and prevents apoptosis, which is mediated by PKC-d-triggered phosphorylation on S360. 8 Ebp1 has also been shown to regulate plant growth. Manipulating the expression level of stEBP1 (homolog of mammalian p48) affects the organ growth of transgenic plants. Specifically, increased levels are associated with increased growth, whereas decreased levels are associated with decreased growth; these effects are dose dependent. During the early stages of organ development, stEBP1 promotes cell prol...

show abstract

“…TIF-IA-GTP binds ErbB3-binding protein 1 (Ebp1), and in T cells, the presence of Ebp1 is important for the retention of TIF-IA at the site of rRNA synthesis in the nucleolus [47]. Therefore, the binding of TIF-IA to GTP may also be important in its regulation of ribosomal RNA synthesis.…”

Section: Tif-ia As a Transcription Factormentioning

confidence: 99%

TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis

Jin

Zhou

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

View full text Add to dashboard Cite

Cancer cells devote the majority of their energy consumption to ribosome biogenesis, and preribosomal RNA transcription accounts for 30-50% of all transcriptional activity. This aberrantly elevated biological activity is an attractive target for cancer therapeutic intervention if approaches can be developed to circumvent the development of side effects in normal cells. TIF-IA is a transcription factor that connects RNA polymerase I with the UBF/SL-1 complex to initiate the transcription of pre-ribosomal RNA. Its function is conserved in eukaryotes from yeast to mammals, and its activity is promoted by the phosphorylation of various oncogenic kinases in cancer cells. The depletion of TIF-IA induces cell death in lung cancer cells and mouse embryonic fibroblasts but not in several other normal tissue types evaluated in knock-out studies. Furthermore, the nuclear accumulation of TIF-IA under UTP down-regulated conditions requires the activity of LKB1 kinase, and LKB1-inactivated cancer cells are susceptible to cell death under such stress conditions. Therefore, TIF-IA may be a unique target to suppress ribosome biogenesis without significantly impacting the survival of normal tissues.

show abstract

Regulation of ribosomal RNA synthesis in T cells: requirement for GTP and Ebp1

Abstract: Key Points MPA suppresses ribosomal RNA (rRNA) synthesis and cell proliferation in T cells through TIF-IA, a GTP binding protein. The combination of MPA and sotrastaurin potently suppresses T-cell proliferation and inhibits IL-2 secretion through TIF-IA and ErbB3-binding protein 1 (Ebp1).

Cited by 34 publications

References 54 publications

Expression and Role of the ErbB3-Binding Protein 1 in Acute Myelogenous Leukemic Cells

Expression and Role of the ErbB3-Binding Protein 1 in Acute Myelogenous Leukemic Cells

Opposing roles of the two isoforms of ErbB3 binding protein 1 in human cancer cells

TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis

Contact Info

Product

Resources

About