Molecule Information

General Information of the Molecule (ID: Mol01886)

• Name: Insulin induced gene 1 (INSIG1) ,Homo sapiens
• Synonyms: INSIG1
• Molecule Type: Protein
• Gene Name: INSIG1
• Gene ID: 3638
• Location: chr7:155,297,776-155,310,235[+]
• Sequence:
  MPRLHDHFWSCSCAHSARRRGPPRASAAGLAAKVGEMINVSVSGPSLLAAHGAPDADPAP
  RGRSAAMSGPEPGSPYPNTWHHRLLQRSLVLFSVGVVLALVLNLLQIQRNVTLFPEEVIA
  TIFSSAWWVPPCCGTAAAVVGLLYPCIDSHLGEPHKFKREWASVMRCIAVFVGINHASAK
  LDFANNVQLSLTLAALSLGLWWTFDRSRSGLGLGITIAFLATLITQFLVYNGVYQYTSPD
  FLYIRSWLPCIFFSGGVTVGNIGRQLAMGVPEKPHSD
• 3D-structure: PDB ID: 4J81; Classification: Protein transport; Method: X-ray diffraction; Resolution: 1.75 Å
• Function: Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR. Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. Binds oxysterol, including 25-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum. In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG1 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligases AMFR/gp78 and/or RNF139. Also regulates degradation of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78.
• Uniprot ID: INSI1_HUMAN
• Ensembl ID: ENSG00000186480
• HGNC ID: HGNC:6083

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) 1 drug(s) in total

Fluvastatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [ICD-11: 2C60.3] [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Fluvastatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.46E-03; Fold-change: 2.88E-02; Z-score: 2.86E+00
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Steroid biosynthesis signaling pathway; Activation; hsa00100
• Cell Pathway Regulation: Terpenoid bacKbone biosynthesis signaling pathway; Activation; hsa00900
• Cell Pathway Regulation: Steroid hormone biosynthesis signaling pathway; Activation; hsa00140
• In Vitro Model: MCF-10A-neoT cells; Breast; Homo sapiens (Human); CVCL_5554
• In Vivo Model: SV40 C3TAg transgenic mouse model; Mus musculus
• Experiment for Molecule Alteration: Clariom D RNA profiling assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: Acquired resistance to fluvastatin is mediated by restorative upregulation of cholesterol biosynthesis pathway genes.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

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: 4.46E-03; Fold-change: 2.00E-01; Z-score: 2.50E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.34E-02; Fold-change: 2.00E-01; Z-score: 2.89E-01

References

• Ref 1: Gene signature associated with resistance to fluvastatin chemoprevention for breast cancer .BMC Cancer. 2022 Mar 17;22(1):282. doi: 10.1186/s12885-022-09353-2. 10.1186/s12885-022-09353-2