of the Max - MDC

Figure 1. Canonical and non-canonical
IKK/NF-κB signaling pathways result in the
activation of distinct NF-κB dimers and
depend selectively on IKKβ and IKKα. Both
pathways are constitutively activated in
Hodgkin lymphoma cells. Nuclear IKKα may
play additional roles in the control of gene
expression. Homeostasis and activity of the
IKK complex is regulated by the Hsp90-
Cdc37 chaperone complex.
Functional control of IKK by transient interaction
with Hsp90 and Cdc37
The IKK complex undergoes interactions with a number of
regulatory proteins, including the chaperones Cdc37 and
Hsp90. Using an RNAi approach, we found that Cdc37
recruits Hsp90 to the IKK complex in a transitory manner,
preferentially via IKKα. Binding is conferred by N-terminal
as well as C-terminal residues of Cdc37 and results in the
phosphorylation of Cdc37. Cdc37 is essential for the maturation
of de novo synthesized IKKs into enzymatically competent
kinases, but not for assembly of an IKK holocomplex.
Mature IKKs, T-loop phosphorylated after stimulation either
by receptor-mediated signaling or upon DNA damage, further
require Hsp90-Cdc37 to generate an enzymatically activated
state. Thus, Hsp90-Cdc37 acts as a transiently acting
essential regulatory component in IKK signaling cascades.
NF-κB signaling in epithelial organogenesis and
in cardiovascular disease models
To analyze the role of NF-κB in early embryonic development
and in disease models, we have generated NF-κB
repressor and reporter mice. The repressor mice carry a
dominant negative IκBα mutant (IκBα∆N) as a condition al
knock-in allele, while the reporter mice express an NF-κBdriven
β-gal transgene. Using these mice, we could demonstrate
novel morphogenic functions for NF-κB, including
the development of epidermal organs, such as hair follicles
(HF). Epidermal NF-κB acts downstream of ecdodysplasin
(Eda) and its receptor EdaR and is activated in the developing
placodes, but not in the interfollicular epidermis.
During hair follicle (HF) formation, the IKK-NF-κB signaling
cassette is activated downstream of preplacodal signals
(including Wnt/β-catenin) to control placode downgrowth
by stimulating Sonic hedgehog (Shh) and cyclin D1 expression
(see Figure 2). The integration of IKK/NF-κB signaling
into Wnt and Shh signalling networks may have important
implications for the regulation of NF-κB in cancer cells.
In an interdisciplinary cooperation with groups of the cardiovascular
department (including Dominique Müller and
Martin Bergmann), our laboratory has contributed to the in
vivo demonstration of critical roles for NF-κB in hypertension-mediated
cardiac and renal end organ damage. To investigate
the contribution of NF-κB to hypertension-induced
hypertrophy at a genetic level, mice with cardiomyocyterestricted
NF-κB suppression were generated. When challenged
with hypertension-inducing conditions, NF-κB activation
in cardiomyocytes was required to fully induce cardi-
96 Cancer Research