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Post-translational modification of the p53 family members is key to their regulation. Here we report the phosphorylation of TAp63γ, but not ΔNp63γ, by IκB kinase β (IKKβ). Activation of IKKβ by γ radiation or tumor necrosis factor-α led to increased TAp63γ protein levels in cells. IKKβ, but not its kinase-defective mutant IKKβ-K44A, led to this observed stabilization of TAp63γ. This stabilization of TAp63γ in response to γ radiation was significantly decreased in the absence of IKKβ. Phosphorylation of TAp63γ blocks ubiquitylation and possible degradation of this protein. We postulate that phosphorylation of TAp63γ by IKKβ stabilizes the TAp63γ protein by blocking ubiquitylation-dependent degradation of this protein. [ABSTRACT FROM AUTHOR]

Kinase domain (KD) mutations of Bcr-Abl interfering with imatinib binding are the major mechanism of acquired imatinib resistance in patients with Philadelphia chromosome-positive leukemia. Mutations of the ATP binding loop (p-loop) have been associated with a poor prognosis. We compared the transformation potency of five common KD mutants in various biological assays. Relative to unmutated (native) Bcr-Abl, the ATP binding loop mutants Y253F and E255K exhibited increased transformation potency, M351T and H396P were less potent, and the performance of T315I was assay dependent. The transformation potency of Y253F and M351T correlated with intrinsic Bcr-Abl kinase activity, whereas the kinase activity of E255K, H396P, and T315I did not correlate with transforming capabilities, suggesting that additional factors influence transformation potency. Analysis of the phosphotyrosine proteome by mass spectroscopy showed differential phosphorylation among the mutants, a finding consistent with altered substrate specificity and pathway activation. Mutations in the KD of Bcr-Abl influence kinase activity and signaling in a complex fashion, leading to gain- or loss-of-function variants. The drug resistance and transformation potency of mutants may determine the outcome of patients on therapy with Abl kinase inhibitors. [ABSTRACT FROM AUTHOR]