Molecule Information

General Information of the Molecule (ID: Mol01964)

• Name: Fizzy and cell division cycle 20 related 1 (FZR1) ,Homo sapiens
• Synonyms: FZR1; CDH1; FYR; FZR; KIAA1242
• Molecule Type: Protein
• Gene Name: FZR1
• Gene ID: 51343
• Location: chr19:3,506,311-3,538,334[+]
• Sequence:
  MDQDYERRLLRQIVIQNENTMPRVTEMRRTLTPASSPVSSPSKHGDRFIPSRAGANWSVN
  FHRINENEKSPSQNRKAKDATSDNGKDGLAYSALLKNELLGAGIEKVQDPQTEDRRLQPS
  TPEKKGLFTYSLSTKRSSPDDGNDVSPYSLSPVSNKSQKLLRSPRKPTRKISKIPFKVLD
  APELQDDFYLNLVDWSSLNVLSVGLGTCVYLWSACTSQVTRLCDLSVEGDSVTSVGWSER
  GNLVAVGTHKGFVQIWDAAAGKKLSMLEGHTARVGALAWNAEQLSSGSRDRMILQRDIRT
  PPLQSERRLQGHRQEVCGLKWSTDHQLLASGGNDNKLLVWNHSSLSPVQQYTEHLAAVKA
  IAWSPHQHGLLASGGGTADRCIRFWNTLTGQPLQCIDTGSQVCNLAWSKHANELVSTHGY
  SQNQILVWKYPSLTQVAKLTGHSYRVLYLAMSPDGEAIVTGAGDETLRFWNVFSKTRSTK
  VKWESVSVLNLFTRIR
• Function: Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR).
• Uniprot ID: FZR1_HUMAN
• Ensembl ID: ENSG00000105325
• HGNC ID: HGNC:24824

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) 3 drug(s) in total

LY2835219

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: LY2835219
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The ubiquitin (Ub) ligase APC/C, which is activated via the co-activator FZR1, interacts with RB during the G1 phase of cell cycle. More notably, APC/CFZR1 complex degrades S-phase kinase associated protein 2 (SKP2), which inhibits p27, natural CDK inhibitors, resulting in decreased CDK2, CDK4 and CDK6. Accordingly, the loss of FZR1 results in uncontrolled cell cycle progression from G1 to S phase.

Palbociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Palbociclib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The ubiquitin (Ub) ligase APC/C, which is activated via the co-activator FZR1, interacts with RB during the G1 phase of cell cycle. More notably, APC/CFZR1 complex degrades S-phase kinase associated protein 2 (SKP2), which inhibits p27, natural CDK inhibitors, resulting in decreased CDK2, CDK4 and CDK6. Accordingly, the loss of FZR1 results in uncontrolled cell cycle progression from G1 to S phase.

Ribociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Ribociclib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The ubiquitin (Ub) ligase APC/C, which is activated via the co-activator FZR1, interacts with RB during the G1 phase of cell cycle. More notably, APC/CFZR1 complex degrades S-phase kinase associated protein 2 (SKP2), which inhibits p27, natural CDK inhibitors, resulting in decreased CDK2, CDK4 and CDK6. Accordingly, the loss of FZR1 results in uncontrolled cell cycle progression from G1 to S phase.

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: 3.72E-34; Fold-change: 2.64E-01; Z-score: 9.88E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.85E-01; Fold-change: 2.78E-02; Z-score: 9.95E-02

References

• Ref 1: Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review .Int J Cancer. 2019 Sep 1;145(5):1179-1188. doi: 10.1002/ijc.32020. Epub 2019 Jan 7. 10.1002/ijc.32020