TY  - JOUR
AB  - Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics.
AU  - Abbas, R.*
AU  - Hartmann, O.
AU  - Asiss, D.T.*
AU  - Abbas, R.*
AU  - Kagan, J.*
AU  - Kim, H.T.*
AU  - Oren, M.*
AU  - Diefenbacher, M.
AU  - Orian, A.*
AU  - Larisch, S.*
C1  - 70599
C2  - 56003
CY  - Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands
SP  - 1145-1160
TI  - ARTS and small-molecule ARTS mimetics upregulate p53 levels by promoting the degradation of XIAP.
JO  - Apoptosis
VL  - 29
IS  - 7-8
PB  - Springer
PY  - 2024
SN  - 1360-8185
ER  - 

TY  - JOUR
AB  - In the present study, the predictive value of ionising radiation (IR)-induced cell death was tested in peripheral blood lymphocytes (PBLs) and their corresponding Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) in an interlaboratory comparison. PBLs and their corresponding LCLs were derived from 15 tumour patients, that were considered clinically radiosensitive based on acute side-effects, and matched controls. Upon coding of the samples, radiosensitivity of the matched pairs was analysed in parallel in three different laboratories by assessing radiation-induced apoptotic and necrotic cell death using annexin V. All participating laboratories detected a dose-dependent increase of apoptosis and necrosis in the individual samples, to a very similar extent. However, comparing the mean values of apoptotic and necrotic levels derived from PBLs of the radiosensitive cohort with the mean values of the control cohort did not reveal a significant difference. Furthermore, within 15 matched pairs, no sample was unambiguously and independently identified by all three participating laboratories to demonstrate in vitro hypersensitivity that matched the clinical hypersensitivity. As has been reported previously, apoptotic and necrotic cell death is barely detectable in immortalised LCL derivatives using low doses of IR. Concomitantly, the differences in apoptosis or necrosis levels found in primary cells of different individuals were not observed in the corresponding LCL derivatives. All participating laboratories concordantly reasoned that, with the methods applied here, IR-induced cell death in PBLs is unsuitable to unequivocally predict the individual clinical radiosensitivity of cancer patients. Furthermore, LCLs do not reflect the physiological properties of the corresponding primary blood lymphocytes with regard to IR-induced cell death. Their value to predict clinical radiosensitivity is thus highly questionable.
AU  - Greve, B.*
AU  - Dreffke, K.*
AU  - Rickinger, A.
AU  - Könemann, S.*
AU  - Fritz, E.*
AU  - Eckardt-Schupp, F.
AU  - Amler, S.*
AU  - Sauerland, C.*
AU  - Braselmann, H.
AU  - Sauter, W.
AU  - Illig, T.
AU  - Schmezer, P.*
AU  - Gomolka, M.*
AU  - Willich, N.*
AU  - Bölling, T.*
C1  - 805
C2  - 26062
SP  - 226-235
TI  - Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity.
JO  - Apoptosis
VL  - 14
IS  - 2
PB  - Springer
PY  - 2009
SN  - 1360-8185
ER  - 

TY  - JOUR
AB  - The molecular causes for enhanced radiosensitivity of Nijmegen Breakage Syndrome cells are unclear, especially as repair of DNA damage is hardly impeded in these cells. We clearly demonstrate that radiation hypersensitivity is accompanied by enhanced gamma-radiation-induced apoptosis in NBS1 deficient lymphoblastoid cell lines. Differences in the apoptotic behavior of NBS1 (-/-) and NBS1 (+/-) cells are not due to an altered p53 stabilization or phosphorylation in NBS1 (-/-) cells. gamma-radiation-induced caspase-8 activity is increased and visualization of CD95 clustering by laser scanning microscopy shows a significant higher activation of the death receptor in NBS1 (-/-) cells. Further investigation of the molecular mechanisms reveals a role for reactive oxygen species-triggered activation of CD95. These results demonstrate that NBS1 suppresses the CD95 death receptor-dependent apoptotic pathway after gamma-irradiation and evidence is given that this is achieved by regulation of the PI3-K/AKT survival pathway.
AU  - Sagan, D.
AU  - Mörtl, S.
AU  - Müller, I.
AU  - Eckardt-Schupp, F.
AU  - Eichholtz-Wirth, H.
C1  - 1818
C2  - 24742
SP  - 753-767
TI  - Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts.
JO  - Apoptosis
VL  - 12
IS  - 4
PB  - Springer Science + Business Media B.V
PY  - 2007
SN  - 1360-8185
ER  - 

TY  - JOUR
AB  - Cigarette smoking is associated with a plethora of different diseases. Nicotine is the addictive component of cigarette but also acts onto cells of the non-neuronal system, including immune effector cells. Although nicotine itself is usually not referred to as a carcinogen, there is ongoing debate whether nicotine functions as a 'tumor enhancer.' By binding to nicotinic acetylcholine receptors, nicotine deregulates essential biological processes like angiogenesis, apoptosis, and cell-mediated immunity. Apoptosis plays critical roles in a wide variety of physiologic processes during fetal development and in adult tissue and is also a fundamental aspect of the biology of malignant diseases. This review provides an overlook how nicotine influences apoptotic processes and is thus directly involved in the etiology of pathological conditions like cancer and obstructive diseases.
AU  - Zeidler, R.
AU  - Albermann, K.*
AU  - Lang, S.*
C1  - 27652
C2  - 32786
SP  - 1927-1943
TI  - Nicotine and apoptosis.
JO  - Apoptosis
VL  - 12
IS  - 11
PY  - 2007
SN  - 1360-8185
ER  - 

TY  - JOUR
AB  - Fractionated γ-irradiation (15 × 2 Gy in 3 weeks) induces a cellular resistance in HeLa cells against cisplatin exposure but not against irradiation. The mechanisms underlying this cellular resistance are associated with major changes in the TNFR1-dependent transduction pathway. The resistant HeLa/B cells exhibit increased levels of NF-κB with temporally independent regulation of the subunits NF-κB50 and NF-κB65. Blocking IκB degradation by the proteasome inhibitor PSI, which abolishes the release of the active NF-κB protein, induces cell death much more effectively in the parental than in the resistant HeLa/B cells. The translocation of NF-κB does not seem to be affected in a similar manner since masking of the translocation sequence by NF-κB SN50 enhances cisplatin toxicity to the same degree in both cell lines and overcomes drug resistance. Changes in upstream signaling are suggested by increased sensitivity of the parental HeLa cells to cisplatin in the presence of neutralizing anti-TNFR1. In HeLa/B cells, reduced expression of the 50 kDa silencer of death domain, SODD, is accompanied by constitutive overexpression of a 40–42 kDa SODD-like protein. A possible involvement of SODD in cisplatin resistance is discussed, which may shift the balance between life and death in the TNF receptor pathway to increased NF-κB activation.
AU  - Eichholtz-Wirth, H.
AU  - Sagan, D.
C1  - 10357
C2  - 20587
SP  - 255-263
TI  - IkB/NF-kB mediated cisplatin resistance in HeLa cells after low-dose gamma-irradiation is associated with altered SODD expression.
JO  - Apoptosis
VL  - 5
IS  - 3
PY  - 2000
SN  - 1360-8185
ER  -