Targeted disruption of Nemo-like kinase inhibits tumor cell growth by simultaneous suppression of cyclin D1 and CDK2 in human hepatocellular carcinoma

2010 ◽  
Vol 110 (3) ◽  
pp. 687-696 ◽  
Author(s):  
Kwang Hwa Jung ◽  
Jeong Kyu Kim ◽  
Ji Heon Noh ◽  
Jung Woo Eun ◽  
Hyun Jin Bae ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Tumor Cell ◽  
Cyclin D1 ◽  
Human Hepatocellular Carcinoma ◽  
Tumor Cell Growth ◽  
Targeted Disruption

scholarly journals Analysis of wild-type and mutant p21WAF-1 gene activities.

1996 ◽  
Vol 16 (4) ◽  
pp. 1786-1793 ◽  
Author(s):  
J Lin ◽  
C Reichner ◽  
X Wu ◽  
A J Levine
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Tumor Cell ◽  
Cyclin D1 ◽  
Cyclin E ◽  
Growth Suppression ◽  
Nuclear Antigen ◽  
Tumor Cell Growth ◽  
Amino Acid Residues ◽  
Wild Type

The p21WAF-1 gene is positively regulated by the wild-type p53 protein. p21WAF-1 has been shown to interact with several cyclin-dependent kinase complexes and block the activity of G1 cyclin-dependent kinases (cdks). Mutational analysis with the p21WAF-1 gene localized a site, at amino acid residues 21 and 24 in the amino terminus of the protein, for p21WAF-1 binding to cyclins D and E. This region of the protein is conserved (residues 21 to 26) in other p21WAF-1 family members, p27kip-1 and p57kip-2. The same p21WAF-121,24 mutant also fails to bind to cyclin D1-cdk 4 or cyclin E-cdk 2 complexes in vitro, suggesting that amino acid residues 21 and 24 are important for p21WAF-1-cdk-cyclin trimeric complex interactions. The p21WAF-1 wild-type protein will suppress tumor cell growth in culture while p21WAF-1 mutant proteins with defects in residues 21 and 24 fail to suppress tumor cell growth. The overexpression of cyclin D or E in these cells will partially overcome the growth suppression of wild-type p21WAF-1 protein in cells. These results provide evidence that p21WAF-1 acts through cyclin D1-cdk4 and cyclin E-cdk2 complexes in vivo to induce the growth suppression. The p21WAF-1 binding sites for cyclins (residues 21 to 26), cdk2 (residues 49 to 71), and proliferating-cell nuclear antigen (residues 124 to 164) have all been mapped to discrete sites on the protein.

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