FZR1

Official Full Name

fizzy and cell division cycle 20 related 1

Organism

Homo sapiens

GeneID

51343

Background

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in anaphase-promoting complex-dependent catabolic process; mitotic G2 DNA damage checkpoint signaling; and positive regulation of ubiquitin protein ligase activity. Located in nuclear membrane and nucleoplasm. Implicated in developmental and epileptic encephalopathy 109. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

FZR; CDH1; FZR2; HCDH; HCDH1; CDC20C; DEE109;

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Detailed Information

Breast cancer is considered as a heterogeneous disease with distinct subtypes till now, a comprehensive therapeutic strategy was used for treatment of this disease, which included surgery, chemotherapy, endocrine therapy and molecular targeted therapy. However, surgical treatment is still the main choice. For the concept of breast-conserving surgery in the breast cancer therapy, Neoadjuvant chemotherapy is frequently chosen to shrink the tumor size before surgery and lessen damaging to surrounding tissue.

But non-effective neoadjuvant chemotherapy can delay surgery in some degree and develop metastatic tumor spread. However, there is still a scarce of biomarkers for predicting neoadjuvant chemotherapy effect in breast cancer treatment. In clinical research, FZR1 was identified to be a novel biomarker for neoadjuvant chemotherapy by patient cohort evaluation and molecular mechanism investigation. Transcriptomic data analysis gave the indication that expression of FZR1 has a correlation with the neoadjuvant chemotherapy efficacy. For its mechanism, FZR1 may play a pivotal role in chemotherapy drug induced apoptosis and cell cycle arrest. And it stabilizes p53 by impairing phosphorylation at ser15 site. Further demonstration of FZR1 expression of neoadjuvant chemotherapy in animal experiment and patient cohort shows that it can be an effective predictor. So, there is a proposed that FZR1 IHC score is used for neoadjuvant chemotherapy prediction.

Restriction of FZR1 on BRAF oncogenic function

Anaphase-promoting complex/cyclostome (APC/C) plays a pivotal role in cell-cycle progression in M-G1 phases by controlling degradation of cell-cycle regulators, which include DNA replication factors and so on. It has close associations with the APC core complex in late M phase and G1 phase cell-cycle fate decision determinations, and in comparison, with this, its close homolog, CDC20, seems to be with a restricted function in M phase. During the remainder of the cell cycle, FZR1 cut down the interaction between FZR1 and APC core complex for inhibition of APC-dependent function through cyclin-dependent kinases (CDK). Although the FZR1'S excellent APC dependent behavior has been recorded, there is only recent beginning for disclosing FZR1's participation in various cellular processes. APC-independent function of FZR1 has been demonstrated to be able positively regulate ubiquitin E3 ligase activity of SMURF1 to impact osteoblast differentiation. However, it remains to be elusive that how APC-independent functions of FZR1 in tumorigenesis progression.

Mounting evidence indicated that tumor-suppressive role of FZR1, which is coordinated with the notion that FZR1 substrates are frequently overexpressed in a wide spectrum of human malignancies. In addition to this, FZR1 deletions or reduced expression are found in various human tumor tissues. But the molecular mechanisms to explain how loss of FZR1 induces tumorigenesis to remain largely unclear. So, the disclosure of major downstream oncogenic signaling pathways that negatively regulated by the FZR1 tumor suppressor would further define the critical role of FZR1 in tumorigenesis.

Fzr1 Fig 1. There interaction pathways for FZR1/BRAF (Chao Zhang et al. 2017).

References:

Lixin Wan, Ming Chen, Juxiang Cao, Xiangpeng Dai. (2017) 'The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function', Cancer Discovery, doi: 10.1158/2159-8290.CD-20-1656.
Shuo Liu, Haobin Wang, Jun Li. （2020） 'FZR1 as a novel biomarker for breast cancer neoadjuvant chemotherapy prediction'，Cell Death and Disease，doi: 10.1038/s41419-020-03004-9.
Chao Zhang, Gideon Bollag. (2017) 'Anaphase-Promoting Complex Adaptor FZR1/CDH1 Blocks BRAF Signaling Both by Targeting BRAF for Proteolytic Degradation and by Disrupting BRAF Dimerization',Cancer Discov, doi:10.1158/2159-8290.CD-17-0172.

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