Molecule Information

General Information of the Molecule (ID: Mol00527)

• Name: Neurofibromin (NF1) ,Homo sapiens
• Synonyms: Neurofibromatosis-related protein NF-1
• Molecule Type: Protein
• Gene Name: NF1
• Gene ID: 4763
• Location: chr17:31094927-31382116[+]
• Sequence:
  MAAHRPVEWVQAVVSRFDEQLPIKTGQQNTHTKVSTEHNKECLINISKYKFSLVISGLTT
  ILKNVNNMRIFGEAAEKNLYLSQLIILDTLEKCLAGQPKDTMRLDETMLVKQLLPEICHF
  LHTCREGNQHAAELRNSASGVLFSLSCNNFNAVFSRISTRLQELTVCSEDNVDVHDIELL
  QYINVDCAKLKRLLKETAFKFKALKKVAQLAVINSLEKAFWNWVENYPDEFTKLYQIPQT
  DMAECAEKLFDLVDGFAESTKRKAAVWPLQIILLILCPEIIQDISKDVVDENNMNKKLFL
  DSLRKALAGHGGSRQLTESAAIACVKLCKASTYINWEDNSVIFLLVQSMVVDLKNLLFNP
  SKPFSRGSQPADVDLMIDCLVSCFRISPHNNQHFKICLAQNSPSTFHYVLVNSLHRIITN
  SALDWWPKIDAVYCHSVELRNMFGETLHKAVQGCGAHPAIRMAPSLTFKEKVTSLKFKEK
  PTDLETRSYKYLLLSMVKLIHADPKLLLCNPRKQGPETQGSTAELITGLVQLVPQSHMPE
  IAQEAMEALLVLHQLDSIDLWNPDAPVETFWEISSQMLFYICKKLTSHQMLSSTEILKWL
  REILICRNKFLLKNKQADRSSCHFLLFYGVGCDIPSSGNTSQMSMDHEELLRTPGASLRK
  GKGNSSMDSAAGCSGTPPICRQAQTKLEVALYMFLWNPDTEAVLVAMSCFRHLCEEADIR
  CGVDEVSVHNLLPNYNTFMEFASVSNMMSTGRAALQKRVMALLRRIEHPTAGNTEAWEDT
  HAKWEQATKLILNYPKAKMEDGQAAESLHKTIVKRRMSHVSGGGSIDLSDTDSLQEWINM
  TGFLCALGGVCLQQRSNSGLATYSPPMGPVSERKGSMISVMSSEGNADTPVSKFMDRLLS
  LMVCNHEKVGLQIRTNVKDLVGLELSPALYPMLFNKLKNTISKFFDSQGQVLLTDTNTQF
  VEQTIAIMKNLLDNHTEGSSEHLGQASIETMMLNLVRYVRVLGNMVHAIQIKTKLCQLVE
  VMMARRDDLSFCQEMKFRNKMVEYLTDWVMGTSNQAADDDVKCLTRDLDQASMEAVVSLL
  AGLPLQPEEGDGVELMEAKSQLFLKYFTLFMNLLNDCSEVEDESAQTGGRKRGMSRRLAS
  LRHCTVLAMSNLLNANVDSGLMHSIGLGYHKDLQTRATFMEVLTKILQQGTEFDTLAETV
  LADRFERLVELVTMMGDQGELPIAMALANVVPCSQWDELARVLVTLFDSRHLLYQLLWNM
  FSKEVELADSMQTLFRGNSLASKIMTFCFKVYGATYLQKLLDPLLRIVITSSDWQHVSFE
  VDPTRLEPSESLEENQRNLLQMTEKFFHAIISSSSEFPPQLRSVCHCLYQATCHSLLNKA
  TVKEKKENKKSVVSQRFPQNSIGAVGSAMFLRFINPAIVSPYEAGILDKKPPPRIERGLK
  LMSKILQSIANHVLFTKEEHMRPFNDFVKSNFDAARRFFLDIASDCPTSDAVNHSLSFIS
  DGNVLALHRLLWNNQEKIGQYLSSNRDHKAVGRRPFDKMATLLAYLGPPEHKPVADTHWS
  SLNLTSSKFEEFMTRHQVHEKEEFKALKTLSIFYQAGTSKAGNPIFYYVARRFKTGQING
  DLLIYHVLLTLKPYYAKPYEIVVDLTHTGPSNRFKTDFLSKWFVVFPGFAYDNVSAVYIY
  NCNSWVREYTKYHERLLTGLKGSKRLVFIDCPGKLAEHIEHEQQKLPAATLALEEDLKVF
  HNALKLAHKDTKVSIKVGSTAVQVTSAERTKVLGQSVFLNDIYYASEIEEICLVDENQFT
  LTIANQGTPLTFMHQECEAIVQSIIHIRTRWELSQPDSIPQHTKIRPKDVPGTLLNIALL
  NLGSSDPSLRSAAYNLLCALTCTFNLKIEGQLLETSGLCIPANNTLFIVSISKTLAANEP
  HLTLEFLEECISGFSKSSIELKHLCLEYMTPWLSNLVRFCKHNDDAKRQRVTAILDKLIT
  MTINEKQMYPSIQAKIWGSLGQITDLLDVVLDSFIKTSATGGLGSIKAEVMADTAVALAS
  GNVKLVSSKVIGRMCKIIDKTCLSPTPTLEQHLMWDDIAILARYMLMLSFNNSLDVAAHL
  PYLFHVVTFLVATGPLSLRASTHGLVINIIHSLCTCSQLHFSEETKQVLRLSLTEFSLPK
  FYLLFGISKVKSAAVIAFRSSYRDRSFSPGSYERETFALTSLETVTEALLEIMEACMRDI
  PTCKWLDQWTELAQRFAFQYNPSLQPRALVVFGCISKRVSHGQIKQIIRILSKALESCLK
  GPDTYNSQVLIEATVIALTKLQPLLNKDSPLHKALFWVAVAVLQLDEVNLYSAGTALLEQ
  NLHTLDSLRIFNDKSPEEVFMAIRNPLEWHCKQMDHFVGLNFNSNFNFALVGHLLKGYRH
  PSPAIVARTVRILHTLLTLVNKHRNCDKFEVNTQSVAYLAALLTVSEEVRSRCSLKHRKS
  LLLTDISMENVPMDTYPIHHGDPSYRTLKETQPWSSPKGSEGYLAATYPTVGQTSPRARK
  SMSLDMGQPSQANTKKLLGTRKSFDHLISDTKAPKRQEMESGITTPPKMRRVAETDYEME
  TQRISSSQQHPHLRKVSVSESNVLLDEEVLTDPKIQALLLTVLATLVKYTTDEFDQRILY
  EYLAEASVVFPKVFPVVHNLLDSKINTLLSLCQDPNLLNPIHGIVQSVVYHEESPPQYQT
  SYLQSFGFNGLWRFAGPFSKQTQIPDYAELIVKFLDALIDTYLPGIDEETSEESLLTPTS
  PYPPALQSQLSITANLNLSNSMTSLATSQHSPGIDKENVELSPTTGHCNSGRTRHGSASQ
  VQKQRSAGSFKRNSIKKIV
• Function: Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity.
• Uniprot ID: NF1_HUMAN
• Ensembl ID: ENSG00000196712
• HGNC ID: HGNC:7765

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Peripheral nerve sheath tumor [1]

• Resistant Disease: Peripheral nerve sheath tumor [ICD-11: 2F3Y.1]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: sNF02.2 cells; Lung; Homo sapiens (Human); CVCL_K280
• In Vitro Model: Hs 53.T cells; Skin; Homo sapiens (Human); CVCL_0786
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: Ez-Cytox assay
• Mechanism Description: High expression of Bcl-xL in the MPNST cells was caused by a decreased transcriptional expression of the NF1 gene. Down-regulation of the NF1 gene by RNA interference (RNAi) induced an increase in Bcl-xL expression and a decrease in its sensitivity to apoptosis in the benign neurofibroma cell line and primary normal cells.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Peripheral nerve sheath tumor [1]

• Resistant Disease: Peripheral nerve sheath tumor [ICD-11: 2F3Y.1]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: sNF02.2 cells; Lung; Homo sapiens (Human); CVCL_K280
• In Vitro Model: Hs 53.T cells; Skin; Homo sapiens (Human); CVCL_0786
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: Ez-Cytox assay
• Mechanism Description: High expression of Bcl-xL in the MPNST cells was caused by a decreased transcriptional expression of the NF1 gene. Down-regulation of the NF1 gene by RNA interference (RNAi) induced an increase in Bcl-xL expression and a decrease in its sensitivity to apoptosis in the benign neurofibroma cell line and primary normal cells.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Peripheral nerve sheath tumor [1]

• Resistant Disease: Peripheral nerve sheath tumor [ICD-11: 2F3Y.1]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: RAS signaling pathway; Activation; hsa04014
• In Vitro Model: sNF02.2 cells; Lung; Homo sapiens (Human); CVCL_K280
• In Vitro Model: Hs 53.T cells; Skin; Homo sapiens (Human); CVCL_0786
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: Ez-Cytox assay
• Mechanism Description: High expression of Bcl-xL in the MPNST cells was caused by a decreased transcriptional expression of the NF1 gene. Down-regulation of the NF1 gene by RNA interference (RNAi) induced an increase in Bcl-xL expression and a decrease in its sensitivity to apoptosis in the benign neurofibroma cell line and primary normal cells.

Lenvatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [2]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: FOXO3 signaling pathway; Inhibition; hsa04068
• In Vivo Model: Xenograft-nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Quantitative RT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay; Transwell invasion assay
• Mechanism Description: With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance.

Tretinoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Neuroblastoma [3], [4]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Resistant Drug: Tretinoin
• Molecule Alteration: Alteration; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Activation; hsa04010
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: IMR-5 cells; Brain; Homo sapiens (Human); CVCL_1306
• In Vitro Model: NBL-S cells; Brain; Homo sapiens (Human); CVCL_2136
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: NF1 i.ctivation has been reported in neuroblastoma and confers activation of RAS-MAPk signalling and resistance to retinoic acid.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.07E-09; Fold-change: -1.45E-01; Z-score: -3.48E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.00E-01; Fold-change: 1.54E-01; Z-score: 5.88E-01
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.31E-03; Fold-change: 4.23E-01; Z-score: 1.47E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.18E-02; Fold-change: -1.67E-01; Z-score: -8.65E-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: 1.54E-09; Fold-change: 2.24E-01; Z-score: 1.05E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.02E-32; Fold-change: 2.63E-01; Z-score: 1.24E+00
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 1.75E-01; Fold-change: 2.91E-01; Z-score: 9.18E-01

References

• Ref 1: Inhibition of Bcl-xL by ABT-737 enhances chemotherapy sensitivity in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor cells .Int J Mol Med. 2012 Aug;30(2):443-50. doi: 10.3892/ijmm.2012.1013. Epub 2012 May 29. 10.3892/ijmm.2012.1013
• Ref 2: Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance .Cell Death Discov. 2021 Nov 18;7(1):359. doi: 10.1038/s41420-021-00747-y. 10.1038/s41420-021-00747-y
• Ref 3: Neocortical interneurons: from diversity, strength. Cell. 2010 Jul 23;142(2):189-93. doi: 10.1016/j.cell.2010.07.005.
• Ref 4: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015 Aug;47(8):864-71. doi: 10.1038/ng.3333. Epub 2015 Jun 29.