Michael Purol Sandbox 1: Difference between revisions
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==Cancer== | ==Cancer== | ||
In human osteosarcomas, p19INK4d function has been found to be altered | Loss of INK4 gene product function, particularly that of p16(INK4a), is found in 10-60% of human tumors, suggesting that broadly applicable anticancer therapies might be based on restoration of p16INK4a CDK inhibitory function. Although much less frequent, defects of p19INK4d have also been associated with human cancer (osteosarcomas). [1] In human osteosarcomas, p19INK4d function has been found to be altered by phosphorylation at Ser 66 and Ser 76 and ubiquitination at Lys 62. [5] | ||
==Cancer Prevention== | |||
In a 2005 study by Ceruti et al., researchers determined that in addition to and perhaps even independent of its role as a cell cycle inhibitor, p19INK4d is involved in the maintenence of DNA integrity and, therefore, would contribute to cancer prevention. [3] This study shows that p19INK4d is the only INK4 protein whose expression is induced by UV light in neuroblastoma cells, and that this expression clearly reduces UV-induced (DNA-damage-induced) apoptosis by enhancing cellular ability to repair damaged DNA. [3] | |||
==Low et al. (2009) Study== | ==Low et al. (2009) Study== | ||
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This study took an in-depth look at the structural consequences of phosphorylation at different sites of p19INK4d. Low et al. replaced Phe 86 with a trytophan residue which acted as a fluorescence-sensitive probe within a pseudo-wild type (in stability and function) mutant that displayed a hyperfluorescent intermediate which could be detected in unfolding and folding kinetics, but not at equilibrium conditions. | This study took an in-depth look at the structural consequences of phosphorylation at different sites of p19INK4d. Low et al. replaced Phe 86 with a trytophan residue which acted as a fluorescence-sensitive probe within a pseudo-wild type (in stability and function) mutant that displayed a hyperfluorescent intermediate which could be detected in unfolding and folding kinetics, but not at equilibrium conditions. | ||
Researchers then mimicked known phosphorylation sites with glutamate substitutions at <scene name='Michael_Purol_Sandbox_1/Ser_66/1'>Ser 66</scene> and <scene name='Michael_Purol_Sandbox_1/Ser_76/1'>Ser 76</scene> within ''E. coli'' to test the impact of introduced negative charges at these positions on the structural stability of P19INK4d. Results indicated that | Researchers then mimicked known phosphorylation sites with glutamate substitutions at <scene name='Michael_Purol_Sandbox_1/Ser_66/1'>Ser 66</scene> and <scene name='Michael_Purol_Sandbox_1/Ser_76/1'>Ser 76</scene> within ''E. coli'' to test the impact of introduced negative charges at these positions on the structural stability of P19INK4d. Results indicated that mutants with the glutamate substitutions at Ser 76, as well as mutants with glutamate substitutions at both Ser 66 and 76, were significantly destabilized in comparison to the wild-type protein, while mutants with only a Ser 66 glutamate substitution showed no significant destabilization. In particular, the results supported earlier findings that a negative charge at Ser 76 severely decreases protein stability in AR1 and AR2 by affecting the hydrogen bonding pattern of the adjacent residues, leading to a partial unfolding reaction and higher flexibility in the loop. These findings suggest that phosphorylation or mimetic mutation at Ser 76 position allows ubiquitin ligase to more readily access <scene name='Michael_Purol_Sandbox_1/Lys_62/1'>Lys 62</scene> and thus tag p19INK4d for degradation at the proteasome. [4] | ||
==About this Structure== | |||
1BD8 is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BD8 OCA]. | |||
== | ==Additional Resources== | ||
For additional information, see: [[Cancer]] | |||
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==References== | ==References== | ||
[1] | [1] Baumgartner R, Fernandez-Catalan C, Winoto A, Huber R, Engh RA, Holak TA. (1998). Structure of human cyclin-dependent kinase inhibitor p19(INK4d): comparison to known ankyrin-repeat-containing structures and implications for the dysfunction of tumor suppressor p16(INK4a). Structure with Folding & Design 6,1279-1290. | ||
[2] Brotherton DH, Dhanaraj V, Wick S, Brizuela L, Domaille PJ, Volyanik E, Xu X, Parisini E, Smith BO, Archer SJ and others. (1998). Crystal structure of the complex of the cyclin D dependent kinase Cdk6 bound to the cell-cycle inhibitor p19(INK4d). Nature 395,244-250. | [2] Brotherton DH, Dhanaraj V, Wick S, Brizuela L, Domaille PJ, Volyanik E, Xu X, Parisini E, Smith BO, Archer SJ and others. (1998). Crystal structure of the complex of the cyclin D dependent kinase Cdk6 bound to the cell-cycle inhibitor p19(INK4d). Nature 395,244-250. | ||