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Uses of ubiquitin-specific protease 49

A specific, protease-based technology, applied in the field of biomedicine, can solve problems such as poor efficacy of pancreatic ductal carcinoma, and achieve significant technological progress

Active Publication Date: 2019-05-03
SHANGHAI EAST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a use of ubiquitin-specific protease 49 in the preparation of drugs for preventing or treating pancreatic ductal carcinoma. Or the use of drugs for the treatment of pancreatic ductal carcinoma should solve the technical problem of the poor effect of drugs in the prior art for preventing or treating pancreatic ductal carcinoma

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  • Uses of ubiquitin-specific protease 49
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  • Uses of ubiquitin-specific protease 49

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1 Identification of FKBP5 Interacting Proteins by Tandem Affinity Purification Mass Spectrometry Analysis

[0078] Isolation and identification of protein complex components bound to FKBP5 using tandem affinity purification coupled with mass spectrometry (TAP-MS). Firstly, FKBP5 was constructed into the retroviral vector pMSCVpuro with Flag tag, and the correctness of the constructed new vector was verified by enzyme digestion identification and sequencing. The FKBP5 stable strain was constructed by virus infection, and after puro screening, the expression of the target protein FKBP5 was detected by western. The cell lines stably expressing FKBP5 were amplified in large quantities, and the tandem affinity purification was combined with mass spectrometry analysis to identify the interacting proteins that bind to FKBP5.

[0079] The result is as figure 1 As shown in A, tandem affinity purification combined with mass spectrometry successfully identified multiple ...

Embodiment 2

[0081] Example 2 USP49 can stabilize the protein level of FKBP5

[0082] The ubiquitin-proteasome pathway is an important protein degradation system in cells. Small ubiquitin molecules can mediate their degradation by binding to target proteins, and deubiquitinases (DUBs) are proteases that can reverse this process. Tritinylation of the tagged target protein stabilizes intracellular protein levels. figure 1 It has been confirmed that USP49 can interact with FKBP5. In this example, it is further tested whether USP49 can stabilize the protein level of FKBP5.

[0083] First, USP49 shRNA was used to establish a USP49-depleted stable cell line. Western results showed that, compared with the control, when the stable depleted USP49 protein was knocked out, the protein level of FKBP5 was also down-regulated ( figure 2 A). MG132 is a proteasome inhibitor that can prevent the degradation of target proteins through the ubiquitin-proteasome pathway. When MG132 was added to the USP49 st...

Embodiment 3

[0087] Example 3 USP49 regulates the ubiquitination level of FKBP5 protein

[0088] Co-transfect 293T cells with USP49 overexpression plasmid or USP49 catalytic inactivation mutant plasmid and ub plasmid, add MG132 for 4 hours after 48 hours, collect cells for ubiquitination experiment, the results are as follows image 3 As shown, USP49 wild type can obviously down-regulate the ubiquitination level of FKBP5, but USP49 catalytically inactive mutant loses this function. In addition, the ubiquitination level of FKBP5 was significantly increased when USP49 was stably depleted compared with the control group ( Figure 4 ).

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Abstract

The invention provides an application of USP 49 (ubiquitin-specific protease 49) in preparation of a drug for preventing or treating pancreatic ductal adenocarcinoma. An amino acid sequence of the USP 49 is represented as SEQ ID NO:1. The deubiquitinating enzyme USP49 interacting with FKBP5 protein is provided, a degradation and stabilization mechanism of the FKBP5 protein as well as molecular regulation for an FKBP5-AKT pathway by the deubiquitinating enzyme USP49 is determined, the function and the molecular mechanism of the pathway in the occurrence and development processes of pancreatic ductal adenocarcinoma are provided, new basis is provided for treatment of pancreatic ductal adenocarcinoma, and USP49 has direct guidance significance for personalized medical treatment of pancreatic ductal adenocarcinoma.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a drug for preventing or treating pancreatic ductal carcinoma, in particular to the use of ubiquitin-specific protease 49 in the preparation of a drug for preventing or treating pancreatic ductal carcinoma. Background technique [0002] Pancreatic ductal carcinoma (PDAC) is one of the five deadliest malignant tumors in the world, with a mortality-to-incidence ratio of 0.99:1 and a 5-year survival rate of <5%. For patients with pancreatic cancer, in addition to radical surgery, comprehensive treatment including radiotherapy and chemotherapy is required to improve the curative effect. So far, gemcitabine is still the first-line chemotherapy drug for the treatment of pancreatic cancer. Although its curative effect is only about 20%, there is still no drug that can surpass gemcitabine, and even combined drugs have not significantly improved the curative effect. [0003] Since the beginni...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N9/64C12N15/57A61K38/48A61P35/00
CPCA61K38/00C12N9/6421
Inventor 李昀辉袁健罗坤甜吴晨明尹玉娇李磊陈玉平
Owner SHANGHAI EAST HOSPITAL
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