CRL3IBTK Regulates the Tumor Suppressor Pdcd4 through Ubiquitylation Coupled to Proteasomal Degradation

Pisano, Antonio; Ceglia, Simona; Palmieri, Camillo; Vecchio, Eleonora; Fiume, Giuseppe; Laurentiis, Annamaria de; Mimmi, Selena; Falcone, Cristina; Iaccino, Enrico; Scialdone, Annarita; Pontoriero, Marilena; Masci, Francesca Fasanella; Valea, Rosanna; Krishnan, Shibu; Gaspari, Marco; Cuda, Giovanni; Scala, Giuseppe; Quinto, Ileana

doi:10.1074/jbc.m114.634535

Cited by 27 publications

(41 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistently, we have recently proven that IBtkα is a component of Cul3-dependent E3 Ligase (CRL3), promoting auto-ubiquitination and ubiquitination of Pdcd4, a tumor suppressor protein acting as translation inhibitor of specific mRNAs [10,11]. In particular, the interaction of IBtkα with Pdcd4 occurred upon serum restoration in serum-starved HeLa cells, and resulted in the ubiquitination coupled to proteasomal degradation of Pdcd4, increasing the translation of specific mRNAs through counteraction of Pdcd4 repression [10]. …”

Section: Introductionmentioning

confidence: 77%

“…The experimental approach was to interfere the expression of IBTKα , the major transcript isoform of the IBTK gene, which encodes the IBTK α protein, a component of Cul3-dependent E3 Ligase [10]. Since IBtkα contains the protein-protein interaction domains ankyrin repeats, RCC1 and BTB/POZ, we do not exclude that the depletion of this protein could result in the loss of interaction with several cellular targets, which have yet to be characterized.…”

Section: Discussionmentioning

confidence: 99%

“…Since IBtkα contains the protein-protein interaction domains ankyrin repeats, RCC1 and BTB/POZ, we do not exclude that the depletion of this protein could result in the loss of interaction with several cellular targets, which have yet to be characterized. To date, the only substrate recognized to be ubiquitinated through CRL3 IBTK is Pdcd4 [10]; however, the characterization of the full interactome of IBtkα could reserve expanded regulatory roles of this protein.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells

Fiume

Scialdone

Rizzo

et al. 2016

IJMS

Self Cite

View full text Add to dashboard Cite

The IBTK gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after IBTK knock-down by shRNA transduction. In HeLa cells, 1285 (2.03%) of 63,128 mapped transcripts were differentially expressed in IBTK-shRNA-transduced cells, as compared to cells treated with control-shRNA, with 587 upregulated (45.7%) and 698 downregulated (54.3%) RNAs. In K562 cells, 1959 (3.1%) of 63128 mapped RNAs were differentially expressed in IBTK-shRNA-transduced cells, including 1053 upregulated (53.7%) and 906 downregulated (46.3%). Only 137 transcripts (0.22%) were commonly deregulated by IBTK silencing in both HeLa and K562 cells, indicating that most IBTKα effects on gene expression are cell type-specific. Based on gene ontology classification, the genes responsive to IBTK are involved in different biological processes, including in particular chromatin and nucleosomal organization, gene expression regulation, and cellular traffic and migration. In addition, IBTK RNA interference affected RNA maturation in both cell lines, as shown by the evidence of alternative 3′- and 5′-splicing, mutually exclusive exons, retained introns, and skipped exons. Altogether, these results indicate that IBTK differently modulates gene expression and RNA splicing in HeLa and K562 cells, demonstrating a novel biological role of this protein.

show abstract

Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells

Fiume

Scialdone

Rizzo

et al. 2016

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…We recently identified the ␣ isoform of inhibitor of Bruton's tyrosine kinase (IBTK␣) as being preferentially translated in response to eIF2␣-P and ER stress (20). Although the biological functions of IBTK␣ are not yet understood, it is noted that IBTK␣ contains protein-protein interaction domains, including ankyrin repeats and the BTB/POZ domain, which is suggested to enable IBTK␣ to serve as a substrate adapter for the E3 ubiquitin ligase CUL3 (21,22). In this study, we show that IBTK␣ expression is rapidly induced by PERK upon exposure to saturated FFA and that the ensuing activation of IBTK␣ plays an essential role in phagophore initiation by IBTK␣ assembly into a multisubunit complex with LC3b, SEC16A, and SEC31A at the endoplasmic reticulum exit site (ERES).…”

mentioning

confidence: 99%

Function of inhibitor of Bruton's tyrosine kinase isoform α (IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response

Willy¹,

Young²,

Mosley³

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.

show abstract

“…The human IBTK gene is involved in the stress response and tumor growth [17,18]. It expresses a main protein IBtkα isoform, encoding a substrate receptor of Cullin3 ligase that promotes the proteasome-associated degradation of tumor repressor PDCD4 [19]. IBTK RNA interference affected the wide genome expression and RNA splicing in a cell-type-specific manner [20].…”

Section: Introductionmentioning

confidence: 99%

IBTK Haploinsufficiency Affects the Tumor Microenvironment of Myc-Driven Lymphoma in E-myc Mice

Vecchio

Fiume

Mignogna

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

The tumor microenvironment is a dynamic and interactive supporting network of various components, including blood vessels, cytokines, chemokines, and immune cells, which sustain the tumor cell’s survival and growth. Murine models of lymphoma are useful to study tumor biology, the microenvironment, and mechanisms of response to therapy. Lymphomas are heterogeneous hematologic malignancies, and the complex microenvironment from which they arise and their multifaceted genetic basis represents a challenge for the generation and use of an appropriate murine model. So, it is important to choose the correct methodology. Recently, we supported the first evidence on the pro-oncogenic action of IBTK in Myc-driven B cell lymphomagenesis in mice, inhibiting apoptosis in the pre-cancerous stage. We used the transgenic Eμ-myc mouse model of non-Hodgkin’s lymphoma and Ibtk hemizygous mice to evaluate the tumor development of Myc-driven lymphoma. Here, we report that the allelic loss of Ibtk alters the immunophenotype of Myc-driven B cell lymphomas, increasing the rate of pre-B cells and affecting the tumor microenvironment in Eμ-myc mice. In particular, we observed enhanced tumor angiogenesis, increasing pro-angiogenic and lymphangiogenic factors, such as VEGF, MMP-9, CCL2, and VEGFD, and a significant recruitment of tumor-associated macrophages in lymphomas of Ibtk+/- Eμ-myc compared to Ibtk+/+ Eμ-myc mice. In summary, these results indicate that IBTK haploinsufficiency promotes Myc tumor development by modifying the tumor microenvironment.

show abstract

CRL3IBTK Regulates the Tumor Suppressor Pdcd4 through Ubiquitylation Coupled to Proteasomal Degradation

Cited by 27 publications

References 50 publications

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells

Function of inhibitor of Bruton's tyrosine kinase isoform α (IBTKα) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response

IBTK Haploinsufficiency Affects the Tumor Microenvironment of Myc-Driven Lymphoma in E-myc Mice

Contact Info

Product

Resources

About