engleski

DeltaNp73 stabilizes TAp73 proteins but compromises their function due to inhibitory hetero-oligomer formation

Since inhibitory interactions of two proteins often lead to their stabilization, we asked whether !Np73 can affect TAp73 protein levels. We show here that deltaNp73 isoforms indeed stabilise TAp73 proteins but, in doing so, inhibit their transactivation function. Individual p73 isoforms with variant N- and C-termini differ only moderately in their halflives. However, when co-expressed in various cell types, TAp73 a and b proteins become markedly stabilized by deltaNp73a in a dose-dependent manner. Similar results were seen with !Np73b, albeit the effect is weaker. In contrast, p53 protein fails to accumulate via deltaNp73. Using tetramerization-deficient mutants, we find that the ability of deltaNp73 to mediate TAp73 accumulation largely depends on its tetramerization domain and correlates with its activity to function as a dominant-negative inhibitor of TAp73. In the ongoing debate whether TAp73 is a relevant tumor suppressor, we suggest that increased TAp73 protein levels should be interpreted with caution when levels are the only criteria that can be used to deduce TAp73 activity. This is particularly the case in primary tumors where functional studies are not possible.

deltaNp73; TAp73; halflife; stabilization

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