Molecule Information

General Information of the Molecule (ID: Mol00127)

• Name: DNA-binding factor KBF1 (p105) (NFKB1) ,Homo sapiens
• Synonyms: DNA-binding factor KBF1; EBP-1; Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1
• Molecule Type: Protein
• Gene Name: NFKB1
• Gene ID: 4790
• Location: chr4:102501331-102617302[+]
• Sequence:
  MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYV
  CEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCED
  GICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQA
  EGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIY
  DSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDF
  SPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQ
  RKRQKLMPNFSDSFGGGSGAGAGGGGMFGSGGGGGGTGSTGPGYSFPHYGFPTYGGITFH
  PGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGE
  VTLTYATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQD
  ENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVED
  LLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMM
  SNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGT
  TPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMAT
  SWQVFDILNGKPYEPEFTSDDLLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLG
  LGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQ
  AHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQ
  EGPLEGKI
• Function: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.
• Uniprot ID: NFKB1_HUMAN
• Ensembl ID: ENSG00000109320
• HGNC ID: HGNC:7794

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: Western blot analysis; luciferase reporter assay;ChIP
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kB signaling in CRC.

Disease Class: Colorectal cancer [1]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and activating NF-kB/TS signaling in colorectal cancer.

Disease Class: Colon cancer [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Dual-Luciferase Reporter Assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Disease Class: Liver cancer [3]

• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Sensitive Drug: Fluorouracil
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Boyden chamber assay; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Fotemustine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Endometriosis [4]

• Resistant Disease: Endometriosis [ICD-11: GA10.0]
• Resistant Drug: Fotemustine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: Female Sprague-Dawley rats model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [5]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.G489V
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Disease Class: Lung cancer [5]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Resistant Drug: Gefitinib
• Molecule Alteration: Missense mutation; p.G489V
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Investigative Drug(s) 1 drug(s) in total

Platinum

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [6]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Platinum
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: Caspase 3/7 cleavage assays; Aldefluor assay; MTS assay; Flow cytometric analysis
• Mechanism Description: Blocking the EZH2-interactiing domain of HOTAIR and disrupting the HOTAIR-EZH2 interaction resensitizes cancer cells to clinically relevant cytotoxic chemotherapies, reduces cell invasion and decreases NF-kB transcriptional activity and IL-6 and MMP-9 expression in vivo. NF-kB-mediated transcriptional regulation of HOTAIR induced epigenetic silencing of Ik-Balpha, resulting in a positive feedback loop that ultimately increased NF-kB activation in ovarian cancer.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.70E-46; Fold-change: -4.44E-01; Z-score: -1.65E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.76E-01; Fold-change: 1.15E-01; Z-score: 2.32E-01

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.59E-02; Fold-change: -1.07E-01; Z-score: -2.90E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.25E-07; Fold-change: -1.80E-01; Z-score: -4.68E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 3.92E-01; Fold-change: -2.77E-01; Z-score: -5.27E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.38E-26; Fold-change: -3.22E-01; Z-score: -6.41E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.15E-22; Fold-change: -4.14E-01; Z-score: -7.88E-01

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.13E-01; Fold-change: -7.31E-02; Z-score: -1.72E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.02E-01; Fold-change: -9.12E-02; Z-score: -2.17E-01

ICD Disease Classification 16

Endometriosis [ICD-11: GA10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Endometrium
• The Specified Disease: Endometriosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.55E-01; Fold-change: -6.41E-03; Z-score: -1.31E-02

References

• Ref 1: lncRNA HOTAIR Contributes to 5FU Resistance through Suppressing miR-218 and Activating NF-kB/TS Signaling in Colorectal Cancer. Mol Ther Nucleic Acids. 2017 Sep 15;8:356-369. doi: 10.1016/j.omtn.2017.07.007. Epub 2017 Jul 8.
• Ref 2: miR-15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. Sci Rep. 2017 Jun 23;7(1):4194. doi: 10.1038/s41598-017-04172-z.
• Ref 3: Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKAlpha/NF-kB pathway. Biochem Biophys Res Commun. 2018 Jun 18;501(1):33-40. doi: 10.1016/j.bbrc.2018.04.116. Epub 2018 May 7.
• Ref 4: Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis .Int J Mol Sci. 2021 Jun 1;22(11):5998. doi: 10.3390/ijms22115998. 10.3390/ijms22115998
• Ref 5: Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. doi: 10.1038/nature12065. Epub 2013 Apr 7.
• Ref 6: Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and breast cancer. Sci Rep. 2017 Apr 18;7(1):894. doi: 10.1038/s41598-017-00966-3.