of the Max - MDC

Structure of the Group
Group Leader
Prof. Dr. Peter Daniel
Scientists
Dr. Bernhard Gillissen
Dr. Philipp Hemmati
Dr. Christian Scholz
Dr. Isrid Sturm
Dr. Jana Wendt
Graduate Students
Cindrilla Chumduri
Gabriela Forro
Christian Herrberger
Ana Milojkovic
Anika Müer
Tim Overkamp
Thomas Pretzsch
Technical Assistants
Kerstin Heft
Anja Richter
Antje Richter
Jana Rossius
Josephine Russ
Figure 2. Network of p14 ARF induced stress responses
a-d: Subcellular localization of p14 ARF to the nucleus but not to the
mitochondria. A: Mitochondria are labeled red by stable expression
of a DsRed fusion protein as an organelle marker. B: p14 ARF expression
is found in the nucleus and the nucleoli. C: Overlay for p14 ARF
and mitochondria. D: Overlay for red labelled mitochondria and
DAPI. This experiment shows that p14 ARF must triggers the mitochondrial
apoptosis pathway via an indirect mechanism. This is unlike
the case of p53 which had been described recently to localize not
only to the nucleus but also to the mitochondria where p53 exerts
transcription independent apoptotic functions.
e: Schematic model of cell death and cell cycle regulation by
p14 ARF . Following e.g. oncogenic stress or DNA-damage, p14 ARF
induces mitochondrial apoptosis via the p53-mediated activation of
Bax and/or Bak in p53-proficient cells. These events are subject to
inhibition by anti-apoptotic Bcl-x L . In p53 deficient cells, pro-apoptotic
Bax is dispensable and p14 ARF -induced activation of mitochondria
proceeds in a Bak-dependent manner. Nevertheless, p14 ARF
induces caspase-3/7 activation in the absence of mitochondrial activation
and/or trigering of caspase-9. Finally, non-apoptotic forms of
cell death, i.e. programmed necrosis or autophagy, could be
engaged upon expression of p14ARF. Activation of G1 cell cycle
arrest and senescence strictly depends on the presence of p53 and
p21. Regardless of p53/p21/14-3-3σ dysfunction, p14ARF retains
its capacity to block G2/M cell cycle progression by down-regulation
of cdc2 (cdk-1).
through an indirect mechanism. Such p53-independent
mechanisms of p14 ARF induced apoptosis and arrest in the cell
division cycle represent fail-safe mechanisms that allow for
efficient growth suppression following induction of p14 ARF -
mediated stress responses in p53 pathway deficient cells.
Selected Publications
Gillissen B, Essmann F, Hemmati P, Richter A, Richter A, Öztop
I,Chinnadurai G, Dörken B and Daniel PT.(2007). Mcl-1 mediates
the Bax dependency of Nbk/Bik-induced apoptosis.
J Cell Biol. 179, 701-715.
Hemmati, PG, Güner D, Gillissen B, Wendt J, von Haefen C,
Chinnadurai G, Dörken B, Daniel PT. (2006). Bak functionally
complements for loss of Bax during p14ARF-induced mitochondrial
apoptosis in human cancer cells. Oncogene. 25, 6582-94.
Daniel PT, Koert U, Schuppan J. (2006). Apoptolidin: induction
of apoptosis by a natural product. Angew Chem Int Ed Engl. 45,
872-93.
Sturm I, Stephan C, Gillissen B, Siebert R, Janz M, Radetzki S,
Jung K, Loening S, Dörken B, Daniel PT. (2006) .Loss of the tissue-specific
proapoptotic BH3-only protein Nbk/Bik is a unifying
feature of renal cell carcinoma. Cell Death Differ. 13, 619-27.
Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken
B, Schulze-Osthoff K, Daniel PT. (2003). Induction of cell death
by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely
Bax-dependent mitochondrial pathway. EMBO J. 22,
3580-90.
132 Cancer Research