ABCC1 Gene Editing

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ABCC1 Gene Editing    

Multidrug resistance protein 1 (MRP1/ABCC1) is the second ABC transporter identified in humans and was originally discovered from a doxorubicin-selected drug-resistant lung cancer cell line. ABCC1 is expressed almost ubiquitously in many different tissues and cell types, with high levels in lungs, kidney, testicles, skeletal and cardiac muscle and placenta. Consistent with its expression profile, ABCC1 governs the absorption and disposition of multiple endogenous and exogenous substrates across organs and physiological barriers, and serves to protect tissues from toxic molecules.

Regulation of ABCC1 Expression

A variety of mechanisms play a role in the regulation of ABCC1 expression. ABCC1 promoter contains a putative AP-1 site that interacts with a complex containing c-jun/junD. Besides, collagen/b1 integrin/ERK signaling has recently been shown to up-regulate the expression and function of ABCC1 in vitro. Therefore, the interaction between the Extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK/MAPK) signaling cascade and expression of ABC transporters may potentially represent a crucial pathway in cancer chemoresistance. Several oxidative stress-responsive elements located upstream from the ABCC1 promoter have been identified and it has been shown that the key transcriptional factor of antioxidant responsive element driven genes, NFE2L2 (nuclear factor erythroid 2-like 2 or former NRF2), is involved in the regulation of ABCC1 expression.

ABCC1/MRP1 and Disease Therapy

In the past two decades, the relevance of MRP1 in human health and disease has been firmly established, and it continues to be of considerable preclinical and clinical interest, mostly because of the diversity of drugs (xenobiotics) and physiological molecules that are effluxed by this transporter. Solutes effluxed by ABCC1 include hydrophobic natural product antineoplastic agents. Elevated ABCC1 protein and/or mRNA levels have been confirmed in many hematologic and solid tumors, and in some instances, are predictors of poor response to chemotherapy. So far, the strongest association of MRP1 with unfavorable clinical outcome has been in neuroblastoma. Considerable effort has been expended in developing ways to circumvent drug resistance to improve chemotherapy effectiveness in cancer patients, and numerous small molecules and other molecular entities that target ABCC1 for this purpose have been described.

Transport mechanisms of MRP1/ABCC1.Figure 1. Transport mechanisms of MRP1/ABCC1. (Cole S P C, 2014)

ABCC1 recognizes and effluxes a number of hydrophobic and hydrophilic antineoplastic agents, thereby reducing drug accumulation and causing tumor cells to become resistant. Most studies hold that the cytotoxic vincristine and etoposide are excellent substrates of ABCC1, and this finding is supported by in vivo studies in mice. In contrast, particularly compared with P-glycoprotein, ABCC1 confers relatively low levels of resistance to paclitaxel and vinblastine. In addition, ABCC1 confers resistance to anthracyclines (doxorubicin, epirubicin, daunorubicin), mitoxantrone, methotrexate, and flutamide. Also, ABCC1 (and other ABC transporters, in particular ABCG2) recognizes and transports some of the newer "targeted" anticancer agents that act by modifying components of different signaling pathways that control tumor growth, proliferation, and metastatic potential.

ABCC1 Gene Editing Service

CRISPR/Cas9 PlatformCB, 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 ABCC1 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

  • ABCC1 Gene Knockout: We offer ABCC1 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 that covers from sgRNA design and construct, pronuclear microinjection to Founders genotyping and breeding.

  • ABCC1 Gene Knockin: CRISPR/Cas9 PlatformCB provides the one-stop ABCC1 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of ABCC1 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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References

  1. Peterson B G, et al. High-content screening of clinically tested anticancer drugs identifies novel inhibitors of human MRP1 (ABCC1). Pharmacological Research, 2017, 119:313-326.
  2. Kunická, et al. Importance of ABCC1 for cancer therapy and prognosis. Drug Metabolism Reviews, 2014, 46(3):325-342.
  3. Cole S P C. Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. Journal of Biological Chemistry, 2014, 289(45): 30880-30888.
  4. Cole S P C. Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annual review of pharmacology and toxicology, 2014, 54: 95-117.
For research use only. Not intended for any clinical use.

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