Scientists Reveal that CDK2 Autophagy Provides a Potential Pathway for Cancer Treatment
Scientists reveal that CDK2 autophagy provides a potential pathway for cancer treatment
Cyclin-dependent protein kinase 2 (CDK2) is widely known for its critical role in cell cycle progression. This member is a member of the cyclin-dependent protein kinase (CDK) family and is involved in the regulation of DNA synthesis, G1/S phase transition and G2 progression.
Although the monomeric form of CDK2 is inactive, it becomes active when it forms a functional heterodimeric complex with one of its two regulatory partners, cyclins A and E. CDK2 regulates multiple oncogenic signaling pathways while it regulates a series of transcription factors: SMAD3, FOXM1, FOXO1, ID2, and phosphorylation of UBF, NFY, B-Myb, and MYC.
Not surprisingly, the abnormal activation of CDK2 that occurs in many human cancers leads to uncontrolled cell proliferation during tumor formation. Similarly, carcinogenesis in several cancers has been associated with high levels of cyclin A and E, two regulatory subunits of CDK2. In summary, CDK2 activity and its regulatory subunit activity appear to be important components of tumorigenesis.
Recently, researchers from Zhejiang University published an article entitled "Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells" in the journal Nature Communications, This study identifies the autophagic degradation mechanism of CDK2 protein and provides a potential avenue for the treatment of CDK2-dependent cancers.
The cyclin-dependent kinase 2 (CDK2) complex is significantly overactivated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors of CDK2 are ATP competitors, are either nonspecific or highly toxic, and often fail clinical trials. An alternative approach is to develop non-ATP-competitive inhibitors; they disrupt the interaction between CDK2 and its partners or substrates, resulting in specific inhibition of CDK2 activity.
In this report, the researchers identified two potentially drug-capable pockets located at the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target potentially available drug pockets, the researchers performed LIVS electronic screening of a library of 1,925 FDA-approved drugs.
Using this approach, homoharringtonine (HHT) exhibits high affinity for PPI and strongly disrupts the interaction between CDK2 and cyclins. Furthermore, the researchers demonstrate that HHT induces autophagic degradation of CDK2 protein in cancer cells through the tripartite motif 21 (Trim21), which was confirmed in a mouse model of leukemia and primary human leukemia cells.
In this study, the interaction between CDK2 and its partners was disrupted when HHT bound to CDK2 protein. Subsequent contact with Trim21 appears to cause CDK2 protein degradation through the autophagy-lysosomal system. Degradation of CDK2 by HHT has been observed in in vitro cell studies, in vivo animal models, and primary patient samples.
Although only a few studies have explored the mechanism of CDK2 degradation, the above process may represent a novel CDK2 degradation mechanism. Although all CDKs appear to be maintained at similar levels throughout the cell cycle, different phases of the cell cycle have different rates of cyclin synthesis and degradation.
When these cyclins bind to CDK and regulate their activity, this in turn provides control over cell cycle progression. In this context, the degradation mechanisms that the researchers have identified may open up a potential avenue for CDK2-targeted cancer therapy.
At present, Wuxi Donglin Sci & Tech Development Co.,Ltd. has developed Elisa products related to CDK2, If you want to know information about Elisa kits, you can directly visit the website:
http://www.dldevelop.com/Research-reagent/dl-cdk2-hu.html
http://www.dldevelop.com/Research-reagent/dl-cdk2-ra.html
Cyclin-dependent protein kinase 2 (CDK2) is widely known for its critical role in cell cycle progression. This member is a member of the cyclin-dependent protein kinase (CDK) family and is involved in the regulation of DNA synthesis, G1/S phase transition and G2 progression.
Although the monomeric form of CDK2 is inactive, it becomes active when it forms a functional heterodimeric complex with one of its two regulatory partners, cyclins A and E. CDK2 regulates multiple oncogenic signaling pathways while it regulates a series of transcription factors: SMAD3, FOXM1, FOXO1, ID2, and phosphorylation of UBF, NFY, B-Myb, and MYC.
Not surprisingly, the abnormal activation of CDK2 that occurs in many human cancers leads to uncontrolled cell proliferation during tumor formation. Similarly, carcinogenesis in several cancers has been associated with high levels of cyclin A and E, two regulatory subunits of CDK2. In summary, CDK2 activity and its regulatory subunit activity appear to be important components of tumorigenesis.
Recently, researchers from Zhejiang University published an article entitled "Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells" in the journal Nature Communications, This study identifies the autophagic degradation mechanism of CDK2 protein and provides a potential avenue for the treatment of CDK2-dependent cancers.
The cyclin-dependent kinase 2 (CDK2) complex is significantly overactivated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors of CDK2 are ATP competitors, are either nonspecific or highly toxic, and often fail clinical trials. An alternative approach is to develop non-ATP-competitive inhibitors; they disrupt the interaction between CDK2 and its partners or substrates, resulting in specific inhibition of CDK2 activity.
In this report, the researchers identified two potentially drug-capable pockets located at the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target potentially available drug pockets, the researchers performed LIVS electronic screening of a library of 1,925 FDA-approved drugs.
Using this approach, homoharringtonine (HHT) exhibits high affinity for PPI and strongly disrupts the interaction between CDK2 and cyclins. Furthermore, the researchers demonstrate that HHT induces autophagic degradation of CDK2 protein in cancer cells through the tripartite motif 21 (Trim21), which was confirmed in a mouse model of leukemia and primary human leukemia cells.
In this study, the interaction between CDK2 and its partners was disrupted when HHT bound to CDK2 protein. Subsequent contact with Trim21 appears to cause CDK2 protein degradation through the autophagy-lysosomal system. Degradation of CDK2 by HHT has been observed in in vitro cell studies, in vivo animal models, and primary patient samples.
Although only a few studies have explored the mechanism of CDK2 degradation, the above process may represent a novel CDK2 degradation mechanism. Although all CDKs appear to be maintained at similar levels throughout the cell cycle, different phases of the cell cycle have different rates of cyclin synthesis and degradation.
When these cyclins bind to CDK and regulate their activity, this in turn provides control over cell cycle progression. In this context, the degradation mechanisms that the researchers have identified may open up a potential avenue for CDK2-targeted cancer therapy.
At present, Wuxi Donglin Sci & Tech Development Co.,Ltd. has developed Elisa products related to CDK2, If you want to know information about Elisa kits, you can directly visit the website:
http://www.dldevelop.com/Research-reagent/dl-cdk2-hu.html
http://www.dldevelop.com/Research-reagent/dl-cdk2-ra.html
