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A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

ABSTRACT: RNA-seq Data of HCT116 cells treated with a novel Cereblon E3 ligase modulator

PROVIDER: PRJEB42732 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR6929420.fastq.gz	Fastqsanger.gz
	ERR6929430.fastq.gz	Fastqsanger.gz
	ERR6929440.fastq.gz	Fastqsanger.gz
	ERR6929421.fastq.gz	Fastqsanger.gz
	ERR6929431.fastq.gz	Fastqsanger.gz

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Immunomodulatory drugs (IMiDs)- or cereblon E3 ligase modulator (CELMoD)-induced growth suppression of Adult T-Cell Lymphoma/Leukemia (ATL) cells and the intrinsic rolls of cereblon for down-regulation of target proteins and their down-stream effectors

Project description:Adult T-cell lymphoma/leukemia (ATL) is an aggressive subtype of leukemia/lymphoma caused by human T-cell leukemia virus type-1 (HTLV-1) and existing chemotherapy for ATL remains with extremely poor prognosis. Therefore, more effective therapeutic options are urgent needs for this disease. Since recent two clinical studies proved promising curability of Lenalidomide (LEN, a second-generation immunomodulatory drug [IMiDs]) for ATL patients, we investigated the direct growth-inhibitory machineries of LEN on ATL cells. Among 13 ATL-related cell lines, Hut102 and TL-Om1 exhibited best response to LEN treatment and LEN-induced functional modulation of E3-ubiquitin ligase cereblon (CRBN) induced degradation of hematopoietic-specific ikaros-family transcription factors IKZF1 and IKZF3 followed by suppression of their down-stream effectors IRF4 and c-Myc (both have been implied to promote ATL cell malignancy). Additionally, Hut102 and TL-Om1 displayed impaired expression of IKZF2 (deletion in HuT102 and altered translational variants in TL-Om1). LEN-induced growth inhibition to these two cell-lines seemed to be attributed to functional deprivation of all IKZF1/2/3. While CRBN-knockdown (KD) in HuT102 imposed LEN-resistance, IKZF2-KD in LEN-resistant ED40515 induced LEN sensitivity. DNA microarray analysis on LEN-treated HuT102 and OATL4 (LEN-resistant) displayed distinct LEN-responding transcriptional profiles; restoration of immune competency and oncogenic growth promotion respectively. Oral administration of LEN to HuT102-xenographted SCID mice demonstrated significant reduction of tumor mass. Finally, a novel form of IMiDs or cereblon modulator (CELMoD), iberdomide (IBE) exerted deeper and wider range of growth suppression to ATL cells including IKZF2 down regulation. Altogether, these findings strongly indicate the therapeutic advantages of IMiDs or CELMoD against ATL.

2024-02-15 | GSE221056 | GEO

2024-02-15 | GSE221062 | GEO

Role of the COP1 E3 ligase in ERalpha signaling

Project description:Our study defines the E3 ligase COP1 as a positive modulator of ERalpha-dependent gene transcription. We carried our RNA-Seq experiments with total RNAs from control or COP1-depleted MCF7 cells treated or not with estrogens and identified a signature of genes known to be regulated by estrogens whose transcription is deregulated upon COP1 deficiency.

2022-01-01 | GSE183753 | GEO

EGFR is a target of the tumor suppressor E3-ligase FBXW7

Project description:FBXW7 is and E3 ubiquitin ligase and is highly mutated in colorectal cancer. We used human colon organoids with engineered FBXW7 hotspot mutations to investigate novel targets of E3 ligase activity with a combined transcriptomic and proteomic approach uncovering the EGFR-MAPK pathway as highly regulated by the E3 ligase activity.

2024-04-03 | GSE246896 | GEO

Expression data from comparison of wild type and cereblon knock out murine T-cells

Project description:Thalidomide and other immunomodulatory drugs are effective therapies for certain hematological cancers where they kill tumor cells and stimulate T-cell immunity. These compounds mediate their functions by binding to and altering substrate specificity of cereblon (CRBN), an E3-ubiquitin ligase component of the DDB1/Cul4/Rbx1 complex3-5. Here, we report the results of crbn genetic deficiency in a mouse, which revealed CRBN functions as a suppressor of T-cell receptor (TCR) activation. We used microarrays to analyze the cereblon regulated gene expression changes following activation of wild type or cereblon knock out murine T-cells.

2020-05-06 | GSE81725 | GEO

The Hace1 E3 Ligase Modulates the Activity of Multiple Tumor Suppressive CRL E3 Ligases by binding to CAND1

Project description:The Hace1 E3 ligase is a tumor suppressor in stressed cells. Through unknown mechanisms, Hace1 indirectly targets the cyclin D1 proto-oncogene for proteasomal degradation during nutrient depletion. We now show that Hace1 targets HIF1alpha for VHL-dependent degradation during hypoxia. To better understand these diverse actions we performed mass spectrometry to identify Hace1-interacting proteins. We show that Hace1 interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1) under nutrient depletion and hypoxia. CAND1 binds cullins and prevents their entry into cullin ring E3 ligase (CRL) complexes, thus blocking CRL activity. Hace1 binding releases CUL1/2 from CAND1, facilitating assembly of CRL complexes to degrade cyclin D1 and HIF1alpha, respectively. These findings suggest a broad role for Hace1 in regulating tumor suppressive CRL E3 ligases. In this study, we used gene expression profiling to characterize how Hace1 overexpression affect the transcriptional response to hypoxic stress Using Affymetrix exon-level microarrays, we compared the expression profile of HEK293 cells overexpressing either Hace1 or MSCV vector alone, under hypoxia or normoxia

2011-07-01 | E-GEOD-25452 | biostudies-arrayexpress

Project description:Immunomodulatory drugs (IMiDs)- or cereblon E3 ligase modulator (CELMoD)-induced growth suppression of Adult T-Cell Lymphoma/Leukemia (ATL) cells and the intrinsic rolls of cereblon for down-regulation of target proteins and their down-stream effectors

| PRJNA912679 | ENA

BRCT phosphoprotein recognition, but not E3 ligase activity, is essential for BRCA1 tumor suppression

Project description:It has been recognized that BRCA1, in the form of the BRCA1/BARD1 heterodimer, acting as an ubiquitin E3 ligase offered a possible mechanism to explain its pleiotrophic nature of BRCA1 activity. Our observation that mice lacking BRCA1 enzymatic activity are viable apart from male sterility was unexpected. Our results suggest that the E3 ligase activity of BRCA1 is largely dispensable for normal development and is not essential for all BRCA1 functions. Thus, many of the known and unknown functions of BRCA1 are likely to be mediated independent of its ability to catalyze ubiquitination. The genome copy number patterns were studied on the mice tumors that lacks E3 ubiqitin ligase activity of BRCA1 and were compared to copy number profile of mice lacking p53 and both brca1 and p53. Array CGH was performed using Agilent mouse CGH microarray 244K kit. Genomic DNA isolated from tumor tissue and its corresponding mouse tail were labelled with two different dyes and hybridized simultaneously on to microarray slides to perform comparitive genomic hybridization.

2011-08-25 | E-GEOD-31673 | biostudies-arrayexpress

The E3 SUMO ligase Mms21 controls ribosome biogenesis

Project description:The budding yeast E3 SUMO ligase Mms21, a component of the Smc5-6 complex, regulates sister chromatid cohesion, DNA replication, and DNA repair. We identify a role for Mms21 in ribosome biogenesis. The mms21RINGD mutant exhibits reduced rRNA production, nuclear accumulation of 60S and 40S ribosomal proteins, and elevated Gcn4 translation. Genes involved in ribosome biogenesis and translation are down-regulated in the mms21RINGD mutant. Examining gene expression profile of mms21RINGD mutant compared to wild-type by RNA Seq using Ilumina sequencing

2015-06-13 | E-GEOD-69826 | biostudies-arrayexpress

| PRJNA912688 | ENA