UCHL5 Gene Editing    

Modulators of the ubiquitin-proteasome system (UPS) have recently become attractive targets in cancer therapy. The majority of controlled protein degradation is mediated by UPS, which is a key part of maintaining proteostasis. Proteasome substrates are degraded after their polyubiquitination by E1 to E3 enzymes. Important participants include also deubiquitinating enzymes (DUBs) removing ubiquitin(s) from target proteins. Three DUBs are associated with the proteasome, including ubiquitin C-terminal hydrolase L5 (UCHL5/UCH37), a cysteine protease of the family of ubiquitin C-terminal hydrolases (UCHs). The DUB activity of UCHL5 is induced by its reversible and evolutionarily conserved binding to the Admr1/Rpn13 subunit of the 26S proteasome. The C. elegans homolog of UCHL5, UBH-4, tissue-specifically modulates proteasome activity, also affecting the health and longevity of these animals. UCHL5 function is crucial because UCHL5 knockout in mice is embryonically lethal.

UCHL5 Function

UCHL5 is an important component of the 26S proteasome, which is used to remove distal ubiquitin moieties from ubiquitinated substrates and promote protein degradation in the 26S proteasome. UCHL5 has two major domains, catalytic domain and C-terminal domain (CTD). The catalytic domain maintains a close homology to the same family of DUBs, including UCHL1 and UCHL3. The CTD causes auto-inhibition of UCHL5 activity, which is reactivated when CTD binds to Ub receptor, Rpn13, at the 19S RP. Thus, UCHL5 in complex with Rpn13 at the proteasome displays higher DUB activity than UCHL5 alone. In addition to its role at the proteasome, UCHL5 plays a role in DNA repair or transcription by interacting with Ino80 chromatin remodeling complex at the nucleus. UCHL5 is functionally related to multiple protein complexes and signaling transduction pathways. UCHL5 is involved in the activation of the Wnt, Hedgehog and transforming growth factor-β (TGF-β) signaling pathways. UCHL5 regulates gene transcription and DNA damage repair and replication.

UCHL5 and Cancer

Although UCHL5 substrates are not yet completely understood, several biological evidences support their role in cancer. In cancer and healthy tissues both the expression level and subcellular location of UCHL5 vary greatly. UCHL5 deubiquitinates smoothened, TGF-β, and NF-κB, whose stabilizations contribute to tumor cell survival, migration and invasion. A high UCHL5 expression level predicts early recurrence and promotes cell migration and invasion in hepatocellular carcinoma (HCC). UCHL5 can be a predictor of poor survival in esophageal squamous cell carcinoma (ESCC) after curative resection. UCHL5 is a potential marker of gastric cancer and is also involved in the occurrence and development of cervical cancer, colon cancer and multiple myeloma.

Proteasome inhibitors are successfully used for treatment of multiple myeloma and mantle cell lymphoma, albeit severe side effects may occur, which are related to dose-limiting toxicity and drug resistance, especially during cancer recurrence. Therefore, attention has turned to other modulators of the UPS, including DUBs, as promising treatment targets in cancer. UCHL5 is one of three DUBs on the proteasome that control the fate of poly-ubiquitinated proteins associated with cancer. Therefore, the potent and selective inhibitors for UCHL5 would be important to understand UCHL5 in cancer biology. Pharmacological dual inhibition of UCHL5 and Usp-14 induces cytotoxicity, especially in cancer cells, as well as inhibition of tumor growth. This provides an attractive strategy to overcome resistance to traditional proteasome inhibitors.

UCHL5 Gene Editing Services

CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively UCHL5 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• UCHL5 Gene Knockout: We offer UCHL5 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service covers from sgRNA design and construction, pronuclear microinjection to Founders genotyping and breeding.
• UCHL5 Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop UCHL5 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of UCHL5 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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