TdT interacting factor 1 enhances TdT ubiquitylation through recruitment of BPOZ‐2 into nucleus from cytoplasm

Hayano, Takahide; Koiwai, Kotaro; Ishii, Hisataka; Maezawa, So; Kouda, Kousuke; Motoyama, Takuro; Kubota, Takashi; Koiwai, Osamu

doi:10.1111/j.1365-2443.2009.01358.x

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…TdT contributes to the diversity of immunoglobulins and T-cell receptors in lymphocytes [2], [3]. TdIF1 negatively regulates TdT activity [1], [4], [5] and controls TdT degradation through the Bood POZ-containing gene type-2 (BPOZ-2)-mediated ubiquitin proteasome system [6], [7]. These previous studies showed that TdIF1 controls TdT in lymphocytes at the post-translational level.…”

Section: Introductionmentioning

confidence: 93%

TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

et al. 2013

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TdIF1 was originally identified as a protein that directly binds to DNA polymerase TdT. TdIF1 is also thought to function in transcription regulation, because it binds directly to the transcriptional factor TReP-132, and to histone deacetylases HDAC1 and HDAC2. Here we show that TdIF1 recognizes a specific DNA sequence and regulates gene transcription. By constructing TdIF1 mutants, we identify amino acid residues essential for its interaction with DNA. An in vitro DNA selection assay, SELEX, reveals that TdIF1 preferentially binds to the sequence 5′-GNTGCATG-3′ following an AT-tract, through its Helix-Turn-Helix and AT-hook motifs. We show that four repeats of this recognition sequence allow TdIF1 to regulate gene transcription in a plasmid-based luciferase reporter assay. We demonstrate that TdIF1 associates with the RAB20 promoter, and RAB20 gene transcription is reduced in TdIF1-knocked-down cells, suggesting that TdIF1 stimulates RAB20 gene transcription.

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Section: Introductionmentioning

confidence: 93%

TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

et al. 2013

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“…TdIF1 enhances TdT ubiquitylation by importing Bood POZ containing gene type‐2 (BPOZ‐2) from the cytoplasm to the nucleus (Hayano et al . ), which promotes TdT ubiquitylation through Cullin 3 (CUL3)‐based ubiquitin ligase and degradation by proteasome (Maezawa et al . ).…”

Section: Introductionmentioning

confidence: 99%

Definition of the transcription factor TdIF1 consensus‐binding sequence through genomewide mapping of its binding sites

et al. 2015

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TdIF1 was originally identified as a protein that directly binds to terminal deoxynucleotidyltransferase, TdT. Through in vitro selection assays (SELEX), we recently showed that TdIF1 recognizes both AT-tract and a specific DNA sequence motif, 5 0 -TGCATG-3 0 , and can upregulate the expression of RAB20 through the latter motif. However, whether TdIF1 binds to these sequences in the cells has not been clear and its other target genes remain to be identified. Here, we determined in vivo TdIF1-binding sequences (TdIF1-invivoBMs) on the human chromosomes through ChIP-seq analyses. The result showed a 160-base pair cassette containing 'AT-tract~palindrome (inverted repeat)~AT-tract' as a likely target sequence of TdIF1. Interestingly, the core sequence of the palindrome in the TdIF1-invivoBMs shares significant similarity to the above 5 0 -TGCATG-3 0 motif determined by SELEX in vitro. Furthermore, spacer sequences between AT-tract and the palindrome contain many potential transcription factor binding sites. In luciferase assays, TdIF1 can up-regulate transcription activity of the promoters containing the TdIF1-invivoBM, and this effect is mainly through the palindrome. Clusters of this motif were found in the potential target genes. Gene ontology analysis and RT-qPCR showed the enrichment of some candidate targets of TdIF1 among the genes involved in the regulation of ossification. Potential modes of transcription activation by TdIF1 are discussed.

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“… 39 HDACs are known to modulate multiple processes in chromatin organization, including repressing the transcription of genes mediating apoptosis and the expression of cell cycle regulators such as cyclins and CDKs. 40 However, they can also directly target lysine residues on protein substrates for deacetylation and downregulate protein activity, including p53. 18 Moreover, HDAC1/2 have been identified to be overexpressed in certain cancers, and small molecule HDAC inhibitors (HDACi) are being investigated as lung cancer chemotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

TdIF1: a putative oncogene in NSCLC tumor progression

Zhang

Wang

Huang

et al. 2018

Sig Transduct Target Ther

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TdT-interacting factor 1 (TdIF1) is a ubiquitously expressed DNA- and protein-binding protein that directly binds to terminal deoxynucleotidyl transferase (TdT) polymerase. Little is known about the functional role of TdIF1 in cancer cellular signaling, nor has it previously been identified as aberrant in any type of cancer. We report here for the first time that TdIF1 is abundantly expressed in clinical lung cancer patients and that high expression of TdIF1 is associated with poor patient prognosis. We further established that TdIF1 is highly expressed in human non-small cell lung cancer (NSCLC) cell lines compared to a normal lung cell line. shRNA-mediated gene silencing of TdIF1 resulted in the suppression of proliferation and anchorage-independent colony formation of the A549 adenocarcinoma cell line. Moreover, when these TdIF1-silenced cells were used to establish a mouse xenograft model of human NSCLC, tumor size was greatly reduced. These data suggest that TdIF1 is a potent regulator of lung tumor development. Several cell cycle-related and tumor growth signaling pathways, including the p53 and HDAC1/2 pathways, were identified as participating in the TdIF1 signaling network by in silico analysis. Microarray, transcriptome and protein-level analyses validated p53 and HDAC1/2 modulation upon TdIF1 downregulation in an NSCLC cellular model. Moreover, several other cell cycle regulators were affected at the transcript level by TdIF1 silencing, including an increase in CDKN1A/p21 transcripts. Taken together, these results indicate that TdIF1 is a bona fide tumor-promoting factor in NSCLC and a potential target for therapy.

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TdT interacting factor 1 enhances TdT ubiquitylation through recruitment of BPOZ‐2 into nucleus from cytoplasm

Cited by 5 publications

References 22 publications

TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

TdIF1 Recognizes a Specific DNA Sequence through Its Helix-Turn-Helix and AT-Hook Motifs to Regulate Gene Transcription

Definition of the transcription factor TdIF1 consensus‐binding sequence through genomewide mapping of its binding sites

TdIF1: a putative oncogene in NSCLC tumor progression

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