Molecule Information

General Information of the Molecule (ID: Mol00057)

• Name: Delta-like protein 1 (DLL1) ,Homo sapiens
• Synonyms: Drosophila Delta homolog 1; Delta1; H-Delta-1; UNQ146/PRO172
• Molecule Type: Protein
• Gene Name: DLL1
• Gene ID: 28514
• Location: chr6:170282206-170306565[-]
• Sequence:
  MGSRCALALAVLSALLCQVWSSGVFELKLQEFVNKKGLLGNRNCCRGGAGPPPCACRTFF
  RVCLKHYQASVSPEPPCTYGSAVTPVLGVDSFSLPDGGGADSAFSNPIRFPFGFTWPGTF
  SLIIEALHTDSPDDLATENPERLISRLATQRHLTVGEEWSQDLHSSGRTDLKYSYRFVCD
  EHYYGEGCSVFCRPRDDAFGHFTCGERGEKVCNPGWKGPYCTEPICLPGCDEQHGFCDKP
  GECKCRVGWQGRYCDECIRYPGCLHGTCQQPWQCNCQEGWGGLFCNQDLNYCTHHKPCKN
  GATCTNTGQGSYTCSCRPGYTGATCELGIDECDPSPCKNGGSCTDLENSYSCTCPPGFYG
  KICELSAMTCADGPCFNGGRCSDSPDGGYSCRCPVGYSGFNCEKKIDYCSSSPCSNGAKC
  VDLGDAYLCRCQAGFSGRHCDDNVDDCASSPCANGGTCRDGVNDFSCTCPPGYTGRNCSA
  PVSRCEHAPCHNGATCHERGHRYVCECARGYGGPNCQFLLPELPPGPAVVDLTEKLEGQG
  GPFPWVAVCAGVILVLMLLLGCAAVVVCVRLRLQKHRPPADPCRGETETMNNLANCQREK
  DISVSIIGATQIKNTNKKADFHGDHSADKNGFKARYPAVDYNLVQDLKGDDTAVRDAHSK
  RDTKCQPQGSSGEEKGTPTTLRGGEASERKRPDSGCSTSKDTKYQSVYVISEEKDECVIA
  TEV
• Function: Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner. Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation. Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells. Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor. Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis.
• Uniprot ID: DLL1_HUMAN
• Ensembl ID: ENSG00000198719
• HGNC ID: HGNC:2908

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

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Osteosarcoma [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay; Flow cytometric analysis
• Mechanism Description: miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Osteosarcoma [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay; Flow cytometric analysis
• Mechanism Description: miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Osteosarcoma [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay; Flow cytometric analysis
• Mechanism Description: miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.

Methotrexate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Osteosarcoma [1]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Resistant Drug: Methotrexate
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ATF2/ATF3/ATF4 signaling pathway; Inhibition; hsa04915
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay; Flow cytometric analysis
• Mechanism Description: miR34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. The activity of the ATF2/ATF3/ATF4 pathway was reduced in the miR34a-5p mimic-transfected G-292 cells but increased in the miR34a-5p antagomiRtransfected SJSA-1 cells, hence the ATF2/ATF3/ATF4 pathway was validated to be involved in the OS chemoresistance mediated by miR34a-5p.

References

• Ref 1: MiR-34a-5p promotes multi-chemoresistance of osteosarcoma through down-regulation of the DLL1 gene. Sci Rep. 2017 Mar 10;7:44218. doi: 10.1038/srep44218.