Michael Purol Sandbox 1: Difference between revisions

In a 2005 study by Ceruti et al., researchers determined that, in addition to and 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]

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 both mutants with the glutamate substitutions at Ser 76 only and doubly-substituted mutants with glutamate substitutions at 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 a higher flexibility of the loop.  These findings suggest that phosphorylation or mimetic mutation at Ser 76 position allows ubiquitin ligase to access <scene name='Michael_Purol_Sandbox_1/Lys_62/1'>Lys 62</scene> more easily and thus tag p19INK4d for degradation at the proteasome. [4]