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Abstract:
Melanoma is the most aggressive skin cancer; its prognosis, particularly
in advanced stages, is disappointing largely due to the resistance to
conventional anticancer treatments and high metastatic potential.
NF-kappa B constitutive activation is a major factor for the apoptosis
resistance of melanoma. Several studies suggest a role for the
immunophilin FKBP51 in NF-kappa B activation, but the underlying
mechanism is still unknown. In the present study, we demonstrate that
FKBP51 physically interacts with IKK subunits, and facilitates IKK
complex assembly. FKBP51-knockdown inhibits the binding of IKK gamma to
the IKK catalytic subunits, IKK-alpha and -beta, and attenuates the IKK
catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase
activity, we found that the IKK-regulatory role of FKBP51 involves both
its scaffold function and its isomerase activity. Moreover, FKBP51 also
interacts with TRAF2, an upstream mediator of IKK activation.
Interestingly, both FKBP51 TPR and PPIase domains are required for its
interaction with TRAF2 and IKK gamma, whereas only the TPR domain is
involved in interactions with IKK alpha and beta. Collectively, these
results suggest that FKBP51 promotes NF-kappa B activation by serving as
an IKK scaffold as well as an isomerase. Our findings have profound
implications for designing novel melanoma therapies based on modulation
of FKBP51.
