Tumor Protein 53-Induced Nuclear Protein 1 Enhances p53 Function and Represses Tumorigenesis

Shahbazi, Jeyran; Lock, Richard B.; Liu, Tao

doi:10.3389/fgene.2013.00080

Cited by 80 publications

(69 citation statements)

References 53 publications

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“…However, given the established role of the tumor protein p53 in B-cell differentiation and lymphomagenesis, 56 it is intriguing that 3 of the FOXP1-repressed proapoptotic genes (ie, encoding TP63, TP53INP1, and RASSF6) are tumor suppressors that share the capacity to enhance p53 activity. [57][58][59] Apart from that, p63 expression has been correlated to DLBCL prognosis, 60,61 expression of TP53INP1 is low in MALT lymphomas, 62 and methylation of the RASSF6 promoter has been observed in B-cell acute lymphoid leukemia and chronic lymphoid leukemia. 63,64 Although further studies are needed to determine if and how these proapoptotic genes control B-cell survival and lymphomagenesis, combined the 7 FOXP1-repressed proapoptotic genes clearly have prognostic significance for overall and progression-free survival of DLBCL patients ( Figure 1D); the patients with low expression of the gene signature always have a worse prognosis, which is completely in line with their proapoptotic function and with a potential role in lymphomagenesis.…”

Section: Discussionmentioning

confidence: 99%

FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells

Keimpema

Grüneberg

Mokrý

et al. 2014

Blood

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Key Points• FOXP1 directly represses multiple proapoptotic genes in primary mature human B cells and DLBCL cell lines.• FOXP1 cooperates with NF-kB signaling to promote expansion of primary mature human B cells by inhibition of caspase-dependent apoptosis.The forkhead transcription factor FOXP1 is involved in B-cell development and function and is generally regarded as an oncogene in activated B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma, lymphomas relying on constitutive nuclear factor kB (NF-kB) activity for survival. However, the mechanism underlying its putative oncogenic activity has not been established. By gene expression microarray, upon overexpression or silencing of FOXP1 in primary human B cells and DLBCL cell lines, combined with chromatin immunoprecipitation followed by next-generation sequencing, we established that FOXP1 directly represses a set of 7 proapoptotic genes. Low expression of these genes, encoding the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6, and TP53INP1, and AIM2 and EAF2, is associated with poor survival in DLBCL patients. In line with these findings, we demonstrated that FOXP1 promotes the expansion of primary mature human B cells by inhibiting caspase-dependent apoptosis, without affecting B-cell proliferation. Furthermore, FOXP1 is dependent upon, and cooperates with, NF-kB signaling to promote B-cell expansion and survival. Taken together, our data indicate that, through direct repression of proapoptotic genes, (aberrant) expression of FOXP1 complements (constitutive) NF-kB activity to promote B-cell survival and can thereby contribute to B-cell homeostasis and lymphomagenesis. (Blood. 2014;124(23):3431-3440) IntroductionThe forkhead transcription factor FOXP1 plays an important role in a wide diversity of biological processes, including T-cell development and differentiation 1,2 and B-cell development and function. [3][4][5] Furthermore, FOXP1 has long been recognized as a potential oncogene in various types of B-cell non-Hodgkin lymphomas; however, its mode of oncogenic action is largely unknown. 6,7 In diffuse large B-cell lymphoma (DLBCL) and mucosaassociated lymphoid tissue (MALT) lymphoma, aberrantly high expression of FOXP1 is associated with poor prognosis and FOXP1-positive MALT lymphomas were shown to be at risk of transforming into aggressive DLBCLs. 8,9 This overexpression of FOXP1 can be caused by a t(3;14)(p14;q32) translocation, involving FOXP1 and IgH loci, which has recurrently been observed in MALT lymphoma and activated B-cell-like (ABC) DLBCL.10-13 FOXP1 expression is also frequently upregulated in ABC-DLBCL as a result of trisomy 3 or more restricted focal amplifications, 14 whereas aberrant Myc expression in transformed gastric MALT lymphomas leads to upregulation of FOXP1 due to repression of the FOXP1 targeting miRNA 34a. 15 Furthermore, expression levels of FOXP1 can be used as a discriminator between the ABC and germinal center (GC) subtypes of DLBCL, ...

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Section: Discussionmentioning

confidence: 99%

FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells

Keimpema

Grüneberg

Mokrý

et al. 2014

Blood

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“…TP53INP1 was reported to be downregulated in diverse types of cancer and the decreased expression of TP53INP1 was shown to contribute to the pathogenesis of cancer (26)(27)(28). TP53INP1 therefore has potential as a therapeutic target for cancers.…”

Section: Mir-96 Directly Regulates Tp53inp1 Foxo1 and Foxo3a Expressmentioning

confidence: 99%

MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a

Gao

Wang

2014

Molecular Medicine Reports

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Abstract. MicroRNAs (miRNAs) are a conserved class of small, endogenous, non protein-coding RNA molecules that are capable of regulating gene expression at post-transcriptional levels and are involved in diverse cellular processes, including cancer pathogenesis. It has previously been reported that miRNA-96 (miR-96) is overexpressed in human colorectal cancer (CRC). However, the underlying mechanism of miR-96 regulation in CRC remains to be elucidated. In the present study, miR-96 was confirmed to be upregulated in CRC tissues by reverse transcription quantitative polymerase chain reaction. MTT assay, colony formation assay and cell cycle analysis revealed that miR-96 overexpression led to increased tumor cell viability, colony formation ability and cell cycle progression. By contrast, inhibition of miR-96 resulted in the suppression of cell proliferation. It was also demonstrated that miR-96 reduced the messenger RNA and protein expression levels of tumor protein p53 inducible nuclear protein 1 (TP53INP1), forkhead box protein O1 (FOXO1) and FOXO3a, which are closely associated with cell proliferation. A luciferase reporter assay indicated that miR-96 inhibited luciferase intensity controlled by the 3'UTRs of TP53INP1, FOXO1 and FOXO3a. In conclusion, the results of the present study demonstrated that miR-96 contributed to CRC cell growth and that TP53INP1, FOXO1 and FOXO3a were direct targets of miR-96, suggesting that miR-96 may have the potential to be used in the development of miRNA-based therapies for CRC patients.

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“…Data in Fig. 4B indicate phosphorylation of the Ser9 and Ser15 residues (both trigger p53 activity to induce DNA repair pathways in response to DNA damage (Haas, 2009; Oda et al, 2000; Shahbazi et al, 2013; Xu et al, 2012; Yamaguchi et al, 2001)), as well as Ser46, whose phosphorylation regulates the ability of p53 to induce apoptosis (Oda et al, 2000). The western blot analysis showed that X-ray IR induced phosphorylation of all analyzed serine residues in both HIV-1 chronically infected and parental uninfected cells.…”

Section: Resultsmentioning

confidence: 97%

“…In fact, we have observed presence of Tat after IR when transfecting an epi-Tat construct into lymphocytes (CEM) following IP/WB for presence of Tat after 48 h (data not shown). IR-induced p53 phosphorylation at Ser15 and Ser20 are utilized for DNA repair and release, whereas Ser46 phosphorylation is critical for apoptosis (Haas, 2009; Shahbazi et al, 2013; Yamaguchi et al, 2001). Western blot analysis of chronically-HIV-1 infected T cell line and parental uninfected cells revealed involvement of the mechanism of p53-dependent apoptosis in both infected and uninfected irradiated cells, with the level of phosphorylation of Ser46 residue markedly higher on the p53 protein from infected cells.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

et al. 2015

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The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4+ T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4+ T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4+ T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells.

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Tumor Protein 53-Induced Nuclear Protein 1 Enhances p53 Function and Represses Tumorigenesis

Cited by 80 publications

References 53 publications

FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells

FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells

MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a

Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

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