Research Report 2000 - MDC

Requirement of NF-κB for
growth and survival of
lymphoma and leukemia cells
In collaboration with the research
group of B. Dörken, we have
discovered the crucial role of
constitutive nuclear NF-κB activity in
the viability of malignant cells in
Hodgkin’s disease (HD). NF-κB
counteracts programmed cell death
and, hence, may critically contribute
in the etiology of HD. Similarly,
antiapoptotic effects of NF-κB have
been demonstrated by other groups in
transformed cell lines, primary murine
cells or breast cancer cells.
Constitutive NF-κB activity is further
required for cell cycle progression of
HD cells. However, proliferation of
virally transformed cell lines with an
inactivated retinoblastoma protein
(pRB) checkpoint do not require NFκB
activity. In collaboration with the
group of M. Strauss, we can now
demonstrate with primary nontransformed
cells that NF-κB is, in
fact, also required for growth factor
signaling in normal primary cells and
promotes G 1 to S phase transition by
regulating the RB pathway. NF-κB
activates transcription of the cyclin
D1 promoter in response to serum
stimulation and, thereby, contributes
to pRB phosphorylation. Further
functional connections between NFκB
and cell cycle regulator proteins
are under investigation.
A characteristic feature of HD cells is
the constitutive presence of NF-κB
p50-p65 in the nucleus. Our recent
analysis of Hodgkin cells has shown
that the NF-κB/IκB system is
dysregulated in a cell-autonomous
manner, involving both mutations of
IκB genes and aberrant activation of
the IKK complex. Similar constitutive
NF-κB activation has been found in
acute lymphoblastic leukemia (C-
ALL), again caused by IKK
activation. Further studies are being
performed to elucidate the mechanism
of constitutive NF-κB activation.
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Selected Publications
Hirano, F., Chung, M., Tanaka, H.,
Maruyama, N., Makino, I, Moore,
D.D., and Scheidereit, C. (1998)
Alternative splicing variants of IκBβ
establish differential NF-κB signal
responsiveness in human cells. Mol.
Cell. Biol. 18, 2596-2607.
Hirano, F., Hirano, Y., Tanaka, H.,
Handa, H., Makino, I., and
Scheidereit. C. (1998) Functional
interference of Sp1 and NF-κB
through the same DNA binding site.
Mol. Cell. Biol. 18, 1266-1274.
Krappmann, D., Emmerich, F.,
Kordes, U., Scharschmidt, E., Dörken,
B., and Scheidereit, C. (1999)
Molecular mechanisms of constitutive
NF-κB/Rel activation in
Hodgkin/Reed Sternberg cells.
Oncogene 18, 943-53.
Hinz, M., Krappmann, D., Eichten,
A., Heder, A., Scheidereit, C., and
Strauss, M. (1999) NF-κB function in
growth control: Regulation of cyclin
D1 expression and G 0/G 1 to S phase
transition. Mol. Cell. Biol. 19, 2690-
2698.
Heissmeyer, V., Krappmann, D.,
Wulczyn, F.G., and Scheidereit, C.
(1999) NF-κB p105 is a target of IκB
kinases and controls signal-induction
of Bcl-3-p50 complexes. EMBO J. 18,
4766-4778.
Structure of the Group
Group leader
Dr. Claus Scheidereit
Scientists
Dr. Eunice Hatada*
Dr. Michael Hinz*
Dr. Fuminori Hirano*
Dr. Uwe Kordes*
Dr. Daniel Krappmann
Dr. Stefan Mathas*
Dr. Felix Mehrhof*
Dr. Benjamin Mordmüller*
Dr. Ruth Schmidt-Ullrich
Graduate and undergraduate students
Annette Ahlers
Vigo Heißmeyer
Sebastian Tegethoff*
Technical assistants
Erika Scharschmidt
Sabine Jungmann
Rudolf Dettmer
Karin Ganzel*
Secretariat
Daniela Keyner
* part of the period reported