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Showing NELFB — COBRA1 is a alias.

NELFB

Negative elongation factor B · UniProt Q8WX92

Length
580 aa
Mass
65.7 kDa
Annotated
2026-06-10
16 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NELFB (COBRA1/NELF-B) is a subunit of the NELF complex that controls transcription elongation by stabilizing promoter-proximal RNA Polymerase II and shaping gene-specific output during development (PMID:19340312, PMID:40960263). Through this activity it is essential for early embryogenesis and inner cell mass integrity, where it binds developmental promoters such as Lef1 and modulates promoter-bound Pol II to restrain precocious differentiation (PMID:19340312), and it drives lineage-specific programs in mammary epithelium (PMID:26941120) and in adipocyte differentiation, where it promotes open chromatin and stabilizes Pol II at adipogenic loci (Pparg, Cebpa) to enable adipose tissue formation (PMID:40960263). In the nucleus NELFB functions as a transcriptional antagonist of multiple regulatory pathways: it physically interacts with BRCA1 in a DNA repair-independent manner and antagonizes BRCA1 control of the developmental transcription program (PMID:26941120, PMID:15185750), binds the AP-1 components c-Jun and c-Fos to inhibit AP-1 transcriptional activity (PMID:15530430), and attenuates glucocorticoid receptor-mediated gene induction by reducing GR promoter recruitment (PMID:24097989). Structurally, NELFB forms a defined ternary interface with NELF-C and NELF-E (PMID:37591184). Beyond transcription, NELFB has separable cytoplasmic functions: it shuttles the proteolytic TrkC killer fragment to mitochondria to trigger Bax activation, cytochrome c release, and apoptosis (PMID:24034695), and a cytoplasm-restricted pool interacts with PI3K/AKT to support cell proliferation independently of its Pol II pausing role (PMID:37717699).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Medium

    Establishing that COBRA1 is a nuclear partner and repressor of transcription factors gave it a defined regulatory role, first by showing it binds BRCA1 and inhibits AP-1.

    Evidence Endogenous co-immunoprecipitation and immunofluorescence (BRCA1) plus Co-IP, domain mapping, and reporter assays (c-Jun/c-Fos)

    PMID:15185750 PMID:15530430

    Open questions at the time
    • Whether BRCA1 binding is direct versus complex-mediated was not resolved
    • The mechanism linking AP-1 binding to Pol II elongation control was not established
  2. 2007 Low

    Comparing transcriptomes after COBRA1 versus BRCA1 knockdown asked whether the two factors share gene targets, supporting a common regulatory pathway.

    Evidence shRNA knockdown with gene expression microarray in breast cancer cells

    PMID:18071589

    Open questions at the time
    • Overlap is correlative without direct interaction or epistasis
    • Does not distinguish shared targets from independent regulation of the same genes
  3. 2009 High

    Knockout in mice and ESCs answered whether COBRA1 has a developmental requirement, showing it maintains the undifferentiated state by tuning Pol II at developmental promoters.

    Evidence Knockout mouse, shRNA in ESCs, and ChIP at the Lef1 promoter

    PMID:19340312

    Open questions at the time
    • The full set of direct promoter targets was not mapped
    • How COBRA1 distinguishes genes to pause was not defined
  4. 2013 High

    Two studies expanded NELFB beyond Pol II pausing: one showed it executes dependence-receptor apoptosis, the other that it decelerates glucocorticoid receptor signaling.

    Evidence Co-IP, subcellular fractionation, apoptosis assays, and in vivo chick neural tube silencing (TrkC); shRNA, ChIP, competition assays, and motif mutagenesis (GR)

    PMID:24034695 PMID:24097989

    Open questions at the time
    • The molecular signal triggering NELFB cytoplasmic-to-mitochondrial shuttling in TrkC apoptosis was not defined
    • Whether GR attenuation operates through the NELF pausing complex or independently was not separated
  5. 2016 High

    Conditional mammary knockout with Brca1 epistasis established that BRCA1 antagonizes the COBRA1 transcription program independently of DNA repair, defining their developmental relationship.

    Evidence Tissue-specific Cobra1 KO, Brca1/Cobra1 double-KO genetic suppression, and transcription analysis

    PMID:26941120

    Open questions at the time
    • The biochemical mechanism by which BRCA1 counteracts COBRA1 was not defined
    • Which specific COBRA1 target genes drive the mammary phenotype was not pinpointed
  6. 2018 Medium

    Separation-of-function Brca1 alleles refined the antagonism, showing neither BRCA1 enzymatic nor phospho-recognition activity nor PALB2 rescues Cobra1 loss, narrowing the relevant BRCA1 function.

    Evidence Conditional double-KO mice with Brca1 RING and BRCT mutant alleles and Palb2 deletion

    PMID:29426838

    Open questions at the time
    • The specific BRCA1 domain or activity that opposes COBRA1 remains unidentified
    • Single-lab in vivo result without biochemical reconstitution
  7. 2018 Medium

    Prostate cancer studies showed COBRA1 acts as a positive regulator of androgen receptor target genes, indicating its transcriptional effect is context- and factor-dependent rather than uniformly repressive.

    Evidence siRNA knockdown, overexpression, promoter reporter and proliferation assays under androgen deprivation

    PMID:30036938

    Open questions at the time
    • Whether COBRA1 directly binds AR or its promoters was not shown
    • The mechanistic basis for positive versus negative transcriptional effects was not resolved
  8. 2023 High

    A crystal structure and a separation-of-function study together resolved how NELFB assembles into the NELF complex and uncoupled its cytoplasmic proliferative role from nuclear pausing.

    Evidence X-ray crystallography of the NELF-B/C/E ternary complex; nuclear-exclusion mutants, Co-IP, Pol II ChIP, and membrane-tethered PI3K/AKT rescue

    PMID:37591184 PMID:37717699

    Open questions at the time
    • The cytoplasmic NELFB–PI3K/AKT interaction was not structurally defined
    • How a single protein partitions between nuclear pausing and cytoplasmic signaling functions was not fully explained
  9. 2025 High

    Preadipocyte-specific knockout established a NELFB requirement in adipogenesis, showing it enables open chromatin and Pol II loading at master adipogenic genes, with PPARγ acting downstream.

    Evidence Conditional KO mouse, chromatin accessibility and Pol II ChIP, retroviral Pparg rescue, and rosiglitazone pharmacological rescue

    PMID:40960263

    Open questions at the time
    • How NELFB promotes chromatin opening mechanistically was not defined
    • Whether this depends on the canonical NELF complex was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NELFB selects specific genes for pausing versus activation across tissues, and what governs the partition between its nuclear transcriptional and cytoplasmic apoptotic/proliferative functions.
  • No unifying mechanism explains positive versus negative transcriptional outcomes
  • The trafficking signals controlling nuclear versus cytoplasmic NELFB are undefined
  • No direct biochemical link between the structural NELF interface and tissue-specific phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-5357801 Programmed Cell Death 1
Partners
AKT1BRCA1C-FOSC-JUNNELFCNELFEPIK3CATRKC
Complex memberships
NELF complexNELF-B/C/E ternary complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 NELFB/COBRA1 is required for inner cell mass (ICM) integrity and early embryogenesis; knockout causes embryonic lethality at implantation. In mouse embryonic stem cells, COBRA1 depletion reduces colony formation, increases spontaneous differentiation, and leads to precocious expression of developmental regulators (e.g., Lef1). ChIP shows COBRA1 binds the Lef1 promoter and modulates promoter-bound RNA polymerase II abundance. Knockout mouse model, shRNA knockdown in ESCs, chromatin immunoprecipitation (ChIP) PloS one High 19340312
2016 Tissue-specific deletion of Cobra1 in mammary epithelium blocks ductal morphogenesis, alveologenesis, and lactogenesis. Additional loss of full-length Brca1 largely rescues these developmental defects and restores developmental transcription, demonstrating a DNA repair-independent antagonism between BRCA1 and COBRA1 in controlling the COBRA1-dependent transcription programme during mammary gland development. Conditional (tissue-specific) knockout mice, Brca1/Cobra1 double-knockout genetic epistasis, gene expression analysis Nature communications High 26941120
2013 TrkC killer fragment (TrkC KF), generated by proteolytic cleavage of the dependence receptor TrkC in the absence of NT-3, physically interacts with COBRA1/NELFB. COBRA1 is required for TrkC-induced apoptosis; it shuttles TrkC KF to the mitochondria, where it promotes Bax activation, cytochrome c release, and apoptosome-dependent apoptosis. Co-immunoprecipitation, siRNA knockdown, subcellular fractionation/localization, apoptosis assays (cytochrome c release, Bax activation), in vivo chick neural tube NT-3 silencing Molecular cell High 24034695
2004 COBRA1 physically interacts with AP-1 family members c-Jun and c-Fos; the middle region of COBRA1 binds c-Fos. Ectopic expression of COBRA1 inhibits AP-1 transcriptional activity in a dose-dependent manner, and the c-Fos binding region of COBRA1 is required for this inhibition. Co-immunoprecipitation, reporter gene assays (transfection), siRNA knockdown, domain-deletion mapping Biochemical and biophysical research communications Medium 15530430
2004 COBRA1 localizes to the nucleus in human breast cancer cells and co-immunoprecipitates with endogenous BRCA1, confirming a physical interaction between the two proteins in a cellular context. Immunofluorescence, co-immunoprecipitation with endogenous proteins IUBMB life Medium 15185750
2013 NELFB attenuates glucocorticoid receptor (GR)-mediated gene induction, reduces partial agonist activity of an antagonist, and increases the EC50 of an agonist. NELFB diminishes GR recruitment to promoter regions (by ChIP). NELFB and NELF-A each act independently as competitive decelerators at steps after GR action and before/at reporter gene activity. A conserved protein motif shared by NELF-A and NELF-B is required for full modulatory activity of both subunits. Stable shRNA knockdown, ChIP, competition assay (new assay design), mutagenesis of conserved motif, reporter gene assays The Journal of biological chemistry Medium 24097989
2023 Crystal structure of the human NELF-B/C/E ternary complex was solved at high resolution, revealing detailed inter-subunit interaction interfaces and identifying residues important for the association between NELF-B and NELF-E. X-ray crystallography (crystal structure determination) Biochemical and biophysical research communications High 37591184
2023 NELFB function in cell proliferation can be uncoupled from its role in nuclear Pol II pausing. NELFB mutants sequestered in the cytoplasm still support cell proliferation and part of the NELFB-dependent transcriptome. Cytoplasmic NELFB physically and functionally interacts with prosurvival signaling kinases, most notably PI3K/AKT. Ectopic expression of membrane-tethered PI3K/AKT partially bypasses the role of NELFB in cell proliferation but not Pol II occupancy. Separation-of-function mutagenesis (nuclear exclusion mutations), co-immunoprecipitation, ectopic expression of membrane-tethered PI3K/AKT, Pol II ChIP, cell proliferation assays The Journal of biological chemistry High 37717699
2025 Deletion of Nelfb from preadipocyte lineages in mice causes failure of dermal white adipose tissue (dWAT) and other fat depot formation, perinatal lethality, and reduced expression of adipogenic genes (Pparg, Cebpa, Krox20, Stat3). Nelfb promotes open chromatin structure and stabilizes RNA Pol II binding at these gene loci. Retroviral expression of Pparg in Nelfb-depleted cells restored adipocyte differentiation; treatment of Nelfb-deleted mice with the PPARγ agonist rosiglitazone allowed dWAT formation and prolonged lifespan. Conditional knockout mouse (preadipocyte-specific), chromatin accessibility assays, Pol II ChIP, retroviral rescue (Pparg), pharmacological rescue (rosiglitazone), cell differentiation assays Development (Cambridge, England) High 40960263
2018 The genetic interaction between Brca1 and Cobra1 in mammary gland development is domain- and gene-specific: separation-of-function Brca1 mutations abrogating either its RING domain E3 ligase activity or BRCT domain phospho-recognition do not rescue Cobra1 KO mammary defects, and deletion of Palb2 also does not rescue these defects, unlike full-length Brca1 loss. Conditional double-knockout mice (Brca1 separation-of-function alleles × Cobra1 KO), mammary gland phenotypic analysis Scientific reports Medium 29426838
2018 COBRA1 positively influences androgen receptor (AR) target gene expression and promoter activity in prostate cancer cells; depletion decreases cell viability, proliferation, and anchorage-independent growth, while overexpression of COBRA1 allows AR-positive cells to survive under androgen-deprivation conditions. siRNA knockdown and ectopic overexpression, reporter/promoter activity assays, cell viability/proliferation assays, androgen deprivation experiments International journal of molecular sciences Medium 30036938
2007 Gene expression profiling after shRNA-mediated knockdown of COBRA1 and BRCA1 separately in breast cancer cells reveals a significant overlap in the sets of genes regulated by each factor, supporting shared gene regulatory pathways. shRNA knockdown, gene expression microarray International journal of biological sciences Low 18071589

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mouse cofactor of BRCA1 (Cobra1) is required for early embryogenesis. PloS one 52 19340312
2021 NSUN6, an RNA methyltransferase of 5-mC controls glioblastoma response to temozolomide (TMZ) via NELFB and RPS6KB2 interaction. Cancer biology & therapy 32 34705606
2016 Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. Nature communications 22 26941120
2013 The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment. Molecular cell 20 24034695
2007 Concerted transcriptional regulation by BRCA1 and COBRA1 in breast cancer cells. International journal of biological sciences 16 18071589
2004 COBRA1 inhibits AP-1 transcriptional activity in transfected cells. Biochemical and biophysical research communications 12 15530430
2013 A conserved protein motif is required for full modulatory activity of negative elongation factor subunits NELF-A and NELF-B in modifying glucocorticoid receptor-regulated gene induction properties. The Journal of biological chemistry 11 24097989
2017 Knockdown of COBRA1 decreases the proliferation and migration of hepatocellular carcinoma cells. Oncology reports 9 28112367
2025 Nelfb promotes dermal white adipose tissue formation through RNA polymerase II-mediated adipogenic gene regulation. Development (Cambridge, England) 5 40960263
2023 Structural basis of the human negative elongation factor NELF-B/C/E ternary complex. Biochemical and biophysical research communications 5 37591184
2018 BRCA1 Interacting Protein COBRA1 Facilitates Adaptation to Castrate-Resistant Growth Conditions. International journal of molecular sciences 5 30036938
2004 Characterization of COBRA1 in human breast cancer cell lines using a new polyclonal antibody against COBRA1. IUBMB life 5 15185750
2018 Gene-Specific Genetic Complementation between Brca1 and Cobra1 During Mouse Mammary Gland Development. Scientific reports 4 29426838
2000 COBRA-1, a rationally-designed epoxy-THF containing compound with potent tubulin depolymerizing activity as a novel anticancer agent. Bioorganic & medicinal chemistry letters 4 10866379
2021 Role of NELF-B in supporting epithelial-mesenchymal transition and cell proliferation during hepatocellular carcinoma progression. Oncology letters 2 34539865
2023 An essential signaling function of cytoplasmic NELFB is independent of RNA polymerase II pausing. The Journal of biological chemistry 0 37717699

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