[5-Year-Follow-up of the MEmbeR Multicenter Study on Medical-Occupational Rehabilitation]. / 5-Jahres-Follow-Up der multizentrischen Evaluationsstudie zur medizinisch-beruflichen Rehabilitation (MEmbeR).

In Germany, medical-occupational rehabilitation represents an essential link between rehabilitation programs focusing either on medical or occupational rehabilitation. Its main objective is return to work. The current study presents the vocational integration 5 years after medical-occupational rehabilitation and determines possible prognostic factors for long-term occupational integration. To evaluate the effectiveness of medical-occupational rehabilitation, a 5-year-follow-up interview was conducted with participants (n=105) of the multicenter study on medical-occupational rehabilitation (MEmbeR). As a main result, 76% of the participants were still employed 5 years after medical-occupational rehabilitation and the return to work rate was 57%. Prognostic factors for long-term occupational integration could not be identified. However, a low degree of disability, an unrestricted capacity for teamwork as well as an unrestricted ability to judge might be beneficial factors for a successful reintegration. The high amount of participants who returned to work 5 years after medical-occupational rehabilitation, supports the concept of medical-occupational rehabilitation. However, more studies are needed to identify further factors influencing the outcome.

Outcome of neurological early rehabilitation patients carrying multi-drug resistant bacteria: results from a German multi-center study.

BACKGROUND: Colonization or infection with multi-drug resistant (MDR) bacteria is considered detrimental to the outcome of neurological and neurosurgical early rehabilitation patients. METHODS: In a German multi-center study, 754 neurological early rehabilitation patients were enrolled and and reviewed in respect to MDR status, length of stay (LOS) and the following outcome variables: Barthel Index (BI), Early Rehabilitation Index (ERI), Glasgow Outcome Score Extended (GOSE), Coma Remission Scale (CRS), Functional Ambulation Categories (FAC). RESULTS: The mean age of the study population was 68.0 ± 14.8 years. Upon admission, the following prevalence for MDRs was observed: MRSA (methicillin resistant staphylococcus aureus) 7.0% (53/754), ESBL- (extended spectrum beta-lactamase) producing bacteria strains 12.6% (95/754), VRE (vancomycin resistant enterococci) 2.8% (21/754). Patients colonized or infected with MDR bacteria (MDR+) were significantly more frequently diagnosed with a critical illness polyneuropathy - CIP - than non-colonized (MDR-) patients: 29.0% vs. 14.8%. In addition, they were more frequently mechanically ventilated (MDR+: 55/138, 39.9%; MDR- 137/616, 22.2%). MDR+ patients were referred to rehabilitation earlier, had a longer LOS in early rehabilitation, lower BI on admission and at discharge, lower ERI on admission and lower CRS at discharge than MDR- patients. There was a highly significant correlation of the BI upon admission with the BI at discharge (rs = 0.492, p < 0.001). GOSE at discharge differed significantly between both groups (χ 2-test, p < 0.01). Perhaps of greatest importance, mortality among MDR+ was higher in comparison to MDR- (18.1% vs. 7.6%). CONCLUSIONS: The outcome of neurological early rehabilitation patients colonized or infected with MDR bacteria including MRSA or ESBL producing strains is significantly poorer than by non-colonized patients. There is some evidence that the poor outcome could be related to the higher morbidity and lower functional status upon admission.

Criterion validity and sensitivity to change of the Early Rehabilitation Index (ERI): results from a German multi-center study.

BACKGROUND: Evaluation of functional status is difficult in neurological and neurosurgical early rehabilitation patients. The Early Rehabilitation Index (ERI) was introduced in Germany over 20 years ago, but since then validation studies are lacking. The ERI (range -325 to 0 points) includes highly relevant items including the necessity of intermittent mechanical ventilation or tracheostomy. METHODS: The present paper analyzed data from a German multi-center study, enrolling 754 neurological early rehabilitation patients. Together with ERI, Barthel Index (BI), Glasgow Coma Scale (GCS), Glasgow Outcome Score Extended, Coma Remission Scale (CRS), Functional Ambulation Categories and length of stay were obtained. RESULTS: ERI showed significant improvements from admission to discharge (p < 0.001). In addition, there were significant correlations of the ERI upon admission and at discharge with BI, CRS and GCS. CONCLUSIONS: Evaluation of our study data suggest that the ERI may be used as a valid assessment instrument for neurological and neurosurgical early rehabilitation patients.

[Course of rehabilitation in early neurological/neurosurgical rehabilitation. Results of a 2014 multi-center evaluation in Germany]. / Rehabilitationsverlauf von Patienten in der neurologisch-neurochirurgischen Frührehabilitation.

BACKGROUND: In Germany, neurological-neurosurgical early rehabilitation is well established in the treatment of severe neurological diseases. To develop quality standards, knowledge of the current rehabilitation course is required. PATIENTS AND METHODS: A retrospective analysis was performed on the course of rehabilitation from patients in an early neurological/neurosurgical rehabilitation program in 16 centers from 10 German states. The odds for a good or poor outcome were investigated using a multivariate logistic regression model. RESULTS: Seven hundred and fifty-four patients were included in the study. The average age of the patients was 68 ± 15 years. Of the patients studied, 26 % were on mechanical ventilation commencing their neurological rehabilitation. The average duration of stay was 56 ± 51 days. Weaning rate from mechanical ventilation was 65 % and the rate of weaning from tracheal cannula was 54 %. Mean improvement in the Barthel Index of 17 points, significant reduction of dysphagia (from 62 to 30 %) and depended walking (from 99 to 82 %), and the achievement of phase C (the next stage of rehabilitation) in 38 % can still be counted as signs of successful rehabilitation. During their course of stay, near 10 % of the patients died. Of these, 67 % received solely palliative care. In the multivariate logistic models, the absence of the factor "necessity for mechanical ventilation on admission" (odds ratio 0.61; 95 % confidence interval (CI): 0.42 … 0.89) increased the chance for good outcome and the presence of this factor the risk of dying with an odds ratio of 8.07 (95 % CI: 4.54-14.34). DISCUSSION: In spite of the severity of neurological deficits, significant functional progress has been made. These results could be interpret as positive proof of the efficacy of neurological/neurosurgical early rehabilitation programs.

[The MEmbeR Multicenter Study on medical-occupational rehabilitation]. / Multizentrische Evaluationsstudie zur medizinisch-beruflichen Rehabilitation (MEmbeR).

INTRODUCTION: MEmbeR is a prospective multi-center study on medical-occupational rehabilitation in Germany. METHODS: 196 neurological, psychiatric, orthopaedic, and internal medicine patients from 21 rehabilitation centres all across Germany have been enrolled and followed-up for 2 years after discharge. Primary outcome parameter was defined as return to work. Further, the SF-12 and a Mini-ICF-Rating have been used. RESULTS: Mean age was 34.1 (9.9) years, length of stay 150.0 (223.5) days. Prior to occupational rehabilitation, 69.9% were unable to work, 2 years after discharge only 5.6%. Rate of participants seeking a job was reduced from 19.7% to 3.1%. In summary, 78.1% returned to work. Employed participants were younger (32.8 [9.7] vs. 38.5 [9.4] years, p=0.001) and less disabled (Degree of Disablement [GdB]: 20.0 [31.2] vs. 36.1 [33.7], p<0.05). CONCLUSION: The multicenter cohort study MEmbeR provides further knowledge about the outcome of medical-occupational rehabilitation in Germany.

Zipper-interacting protein kinase is involved in regulation of ubiquitination of the androgen receptor, thereby contributing to dynamic transcription complex assembly.

We have recently identified apoptosis-antagonizing transcription factor (AATF), tumor-susceptibility gene 101 (TSG101) and zipper-interacting protein kinase (ZIPK) as novel coactivators of the androgen receptor (AR). The mechanisms of coactivation remained obscure, however. Here we investigated the interplay and interdependence between these coactivators and the AR using the endogenous prostate specific antigen (PSA) gene as model for AR-target genes. Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. Association of AR and its coactivators with the PSA enhancer or promoter occurred in cycles. Dissociation of AR-transcription complexes was due to degradation because inhibition of the proteasome system by MG132 caused accumulation of AR at enhancer/promoter elements. Moreover, inhibition of degradation strongly reduced transcription, indicating that continued and efficient transcription is based on initiation, degradation and reinitiation cycles. Interestingly, knockdown of ZIPK by siRNA had a similar effect as MG132, leading to reduced transcription but enhanced accumulation of AR at androgen-response elements. In addition, knockdown of ZIPK, as well as overexpression of a dominant-negative ZIPK mutant, diminished polyubiquitination of AR. Furthermore, ZIPK cooperated with the E3 ligase Mdm2 in AR-dependent transactivation, assembled into a single complex on chromatin and phosphorylated Mdm2 in vitro. These results suggest that ZIPK has a crucial role in regulation of ubiquitination and degradation of the AR, and hence promoter clearance and efficient transcription.

[Long-term course of patients in neurological rehabilitation Phase B. Results of the 6-year follow-up in a multicenter study]. / Langzeitverlauf von Patienten der neurologischen Rehabilitation Phase B. Ergebnisse der 6-Jahres-Nachuntersuchung einer Multicenterstudie.

BACKGROUND: After conclusion of emergency care for severe neurological diseases patients in Germany are admitted at an early stage to so-called Phase B rehabilitation. No studies have been carried out on the long-term course of these patients. PATIENTS AND METHODS: In a prospective study in 2002 patients in Phase B from 9 centers were included and follow-up investigations were carried out after 5 and 6 years. Assessment instruments used were the Barthel index, the Rankin scale and the EQ-5D. Factors for the risk of a poor outcome and the chances for a good outcome were evaluated using multivariate logistic regression. RESULTS: A total of 1,280 patients were included in the study. A high age increased the risk of dying with a hazard quotient (HQ) of 1.05 (95% CI: 1.04-1.06) and high point counts in the coma remission scale (HQ 0.93; 95% CI: 0.92-0.96) and Barthel index (HQ 0.97; 95% CI: 0.97-0.98) on discharge reduced the risk of dying after 5 years. The factors swallowing impairment (OR 3.1; 95% CI: 1.7-5.5) and obligatory surveillance at the end of rehabilitation (OR 3.2; 95% CI: 1.2-8.6) increased the risk of a poor result in the Rankin scale 2-4 and the factors communication disorder (OR 5.0; 95% CI: 2.0-12.8) and PEG (percutaneous endoscopic gastrostomy) (OR 19.7; 95% CI: 2.7-144.4) on discharge increased the risk of a reduced health-related quality of life (defined as EQ-5D VAS <70) after 6 years. CONCLUSIONS: If support for bodily functions can be successfully reduced during Phase B rehabilitation, the patients will have a good outcome with respect to 5-year survival. If this is not successful the outcome is unfavorable with respect to survival and with respect to achieving self-sufficiency and health-related quality of life after 6 years.

ZIP kinase plays a crucial role in androgen receptor-mediated transcription.

The androgen receptor (AR) is a ligand-dependent transcription factor that plays a crucial role in the development and homeostasis of the prostate and in prostate cancer. The transcriptional activity of AR is mediated by interaction with multiple co-activators, which serve in chromatin modification or remodeling, or provide a link between specific and general transcription factors. We have identified zipper interacting protein (ZIP) kinase as a novel transcriptional co-activator of the AR. ZIP kinase enhanced expression of AR-responsive promotor/luciferase reporter constructs in a hormone- and kinase-dependent manner. Similar results were obtained for glucocorticoid receptor but not for progesterone receptor and estrogen receptor. Following hormone treatment, AR and ZIP kinase formed physical complexes and associated with the promoter and enhancer of the prostate-specific antigen gene, as revealed by chromatin immunoprecipitation. Strikingly, depletion of ZIP kinase by siRNA led to significant reduction of AR-mediated transactivation. The interaction of ZIP kinase with AR seems to be mediated in part by apoptosis antagonizing transcription factor and in part by direct binding. Interestingly, AR was not phosphorylated by ZIP kinase in vitro, suggesting that it phosphorylates other co-activators or chromatin proteins.

Novel phosphorylation of histone H3 at threonine 11 that temporally correlates with condensation of mitotic and meiotic chromosomes in plant cells.

A novel mitosis-specific phosphorylation site in histone H3 at threonine 11 has been described for mammalian cells. This modification is restricted to the centromeric region while phosphorylation at the classical H3 sites, Ser10 and Ser28 occurs along the entire chromosomal arms. Using phosphorylation state-specific antibodies we found that phosphorylation at threonine 11 occurs also in plant cells, during mitosis as well as meiosis. However, in contrast to animal cells, ph(Thr11)H3 was distributed along the entire length of condensed chromosomes, whereas H3 phosphorylated at Ser10 and Ser28 appeared to be restricted to centromeric/pericentromeric chromatin. Phosphorylation at Thr11 started in prophase and ended in telophase, it correlated with the condensation of mitotic and meiotic chromosomes and was independent of the distribution of late replicating heterochromatin and Giemsa-banding positive regions. Interestingly, treatment of cells with the phosphatase inhibitor cantharidin revealed a high level of Thr11 phosphorylation in interphase cells, in this case particularly in pericentromeric regions. These data show that histone modifications are highly dynamic. Moreover, animal and plant organisms may have evolved individual histone codes.

The death associated protein (DAP) kinase homologue Dlk/ZIP kinase induces p19ARF- and p53-independent apoptosis.

Dlk/ZIP kinase is one of five members of the death associated protein (DAP) kinase family. DAP kinase is able to induce apoptosis in a p19ARF/p53-dependent manner. We elucidated the potential role of the p19ARF/p53 pathway in Dlk/ZIP kinase-triggered cell death. Overexpression of a constitutively pro-apoptotic form of Dlk/ZIP kinase induced apoptosis in rat fibroblast cells which express wild-type p19ARF and p53. Cell death was characterised by apoptotic membrane blebbing, mitochondrial depolarisation, cytochrome c release and activation of caspase-3. However, Dlk/ZIP kinase-triggered cell death was also observed in p19ARF-deficient and p53-deficient mouse fibroblast cells. Quantitative analysis revealed that the status of p53 had no major influence on cellular susceptibility to Dlk/ZIP kinase-triggered cell death. Loss of p53 did not prevent Dlk/ZIP kinase-induced mitochondrial membrane depolarisation and release of cytochrome c. Furthermore, overexpression of Dlk/ZIP kinase did not lead to an increased expression of pro-apoptotic p53 target genes in either cell line. These data suggest that Dlk/ZIP kinase is able to trigger the mitochondrial apoptosis pathway independent of the p19ARF/p53 signalling pathway.

Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway.

Dlk/ZIP kinase is a member of the Death Associated Protein (DAP) kinase family of pro-apoptotic serine/threonine kinases that have been implicated in regulation of apoptosis and tumour suppression. Expression of both Dlk/ZIP kinase and its interaction partner Par-4 is maintained in four medulloblastoma cell lines investigated, whereas three of seven neuroblastoma cell lines have lost expression of Par-4. Overexpression of a constitutively pro-apoptotic deletion mutant of Dlk/ZIP kinase induced significant apoptosis in D283 medulloblastoma cells. Cell death was characterized by apoptotic membrane blebbing, and a late stage during which the cells had ceased blebbing and were drastically shrunken or disrupted into apoptotic bodies. Over-expression of the anti-apoptotic Bcl-xL protein had no effect on Dlk/ZIP kinase-induced membrane blebbing, but potently inhibited Dlk/ZIP kinase-induced cytochrome c release and transition of cells to late stage apoptosis. Treatment with caspase inhibitors delayed, but did not prevent entry into late stage apoptosis. These results demonstrate that Dlk/ZIP kinase-triggered apoptosis involves the mitochondrial apoptosis pathway. However, cell death proceeded in the presence of caspase inhibitors, suggesting that Dlk/ZIP kinase is able to activate alternative cell death pathways. Alterations of signal transduction pathways leading to Dlk/ZIP kinase induced apoptosis or loss of expression of upstream activators could play important roles in tumour progression and metastasis of neural tumours.

Interaction of SV40 large T antigen with components of the nucleo/cytoskeleton.

The SV40 large T antigen is a viral oncoprotein which performs multiple interactions with cellular factors to achieve a proliferative state required for viral replication as well as for transformation. The major targets in this scenario are members of the Rb family, pRb, p107, and p130, and tumor suppressor protein p53. These interactions of large T with Rb proteins and p53 are required but not sufficient for transformation. To search for unknown interaction partners of large T that might participate in its transforming activity we employed the yeast two-hybrid system. Screening a cDNA library from a large T-induced brain tumor cell line revealed a total of 86 positive clones representing 37 individual clones. Of these, four clones were selected for further analyses. Interestingly, the cDNA inserts of these clones coded for different components of the cytoskeleton, lamin C, laminin gamma1, thymosin beta4, and gelsolin. Complex formation between large T and these proteins was confirmed in vitro. Interaction of large T with these components might influence activities such as intracellular transport, signal transduction, adhesion, or migration.

Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study.

BACKGROUND: Functional disability is generally caused by hemiplegia after stroke. Physiotherapy used to be the only way of improving motor function in such patients. However, administration of amphetamines in addition to exercise improves motor recovery in animals, probably by increasing the concentration of norepinephrine in the central nervous system. Our aim was to ascertain whether levodopa could enhance the efficacy of physiotherapy after hemiplegia. METHODS: We did a prospective, randomised, placebo-controlled, double-blind study in which we enrolled 53 primary stroke patients. For the first 3 weeks patients received single doses of levodopa 100 mg or placebo daily in combination with physiotherapy. For the second 3 weeks patients had only physiotherapy. We quantitatively assessed motor function every week with Rivermead motor assessment (RMA). FINDINGS: Six patients were excluded from analyses because of non-neurological complications. Motor recovery was significantly improved after 3 weeks of drug intervention in those on levodopa (RMA improved by 6.4 points) compared with placebo (4.1), and the result was independent of initial degree of impairment (p<0.004). The advantage of the levodopa group was maintained at study endpoint 3 weeks after levodopa was stopped. At the end of the study the total RMA score gain for the levodopa group was 8.2 points compared with 5.7 in the placebo group (p=0.020). INTERPRETATION: A single dose of levodopa is well tolerated and, when given in combination with physiotherapy, enhances motor recovery in patients with hemiplegia. In view of its minimal side-effects, levodopa will be a possible add- on during stroke rehabilitation.

Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.

Identification of amplified genes from SV40 large T antigen-induced rat PNET cell lines by subtractive cDNA analysis and radiation hybrid mapping.

Primitive neuroectodermal tumors (PNETs) such as human medulloblastomas are genetically heterogeneous and therefore poorly understood. In a rat model the SV40 large T antigen was used to induce neoplasms with characteristic features of PNETs. Tumor development requires a latency period of 8-11 months implicating secondary genetic alterations. To identify such secondary alterations we performed comparative analyses of two phenotypically identical PNET-derived cell lines. Indeed, these cell lines displayed distinct high-level amplification sites. Using a combination of subtractive cDNA analysis and radiation hybrid mapping we have now identified genes in the amplicon regions of the two cell lines. Interestingly, one of these genes encodes the rat homolog of a cytosolic branched chain aminotransferase (BCAT(C)) previously shown to be amplified in a mouse teratocarcinoma cell line. We propose that this simple cloning strategy may serve as a powerful tool for the isolation of genes implicated in known chromosomal aberrations in primary tumors and tumor cell lines.

The DAP kinase family of pro-apoptotic proteins: novel players in the apoptotic game.

The DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP kinase family members are involved in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352-358, 2001.

[Familial myoclonus-dystonia syndrome associated with panic attacks]. / Familiäres Myoklonus-Dystonie-Syndrom assoziiert mit Panikattacken.

We report a case of autosomal dominantly inherited dystonia and panic attacks to discuss successful treatment of a common serotonergic pathology with medication. The objective analysis of the movement disorder was done by Optotrak. First we demonstrate a reduction of the myoclonus by L-5-hydroxytryptophan, which inhibits after 11 months. After changing the medication to Nefadozone, the myoclonus and the frequency of panic attacks were reduced.

Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation.

SV40 large T antigen-induced primitive neuroectodermal tumors of the rat provide a model system to study induction and progression of primitive neuroectodermal tumors at the molecular level. A cell line derived from such a tumor reproducibly gave rise to malignant derivatives that ceased large T-antigen expression but harbored a mutant p53 allele with a common mutation at Cys(174) to Tyr (C174Y). To determine whether this p53 mutation contributes to tumor progression, we analyzed mutant C174Y functionally. Co-transfection experiments in Saos-2 cells with mutant or wild-type p53 and reporter genes linked to various p53-responsive promoters revealed that mutant C174Y failed to transcriptionally transactivate the Mdm2, Waf1, Cyclin G and Bax promoters. Loss of transcriptional activation correlated with loss of DNA-binding activity. Moreover, mutant C174Y exhibited a dominant negative effect on co-expressed wild-type p53. The ability of mutant p53 to repress the viral RSV, LTR or SV40 early promoters or the cellular fos promoter was likewise impaired. In contrast, it showed even induction of the fos promoter. Consistent with these observations, mutant C174Y was non-functional in the suppression of Saos-2 cell growth and even conferred a growth advantage to the cells. Surprisingly, mutant C174Y was also impaired in nuclear transport, as revealed by immunofluorescence analyses. Taken together, our results demonstrate that mutant C174Y possesses features that can positively contribute to cancer progression.

C-terminal truncation of Dlk/ZIP kinase leads to abrogation of nuclear transport and high apoptotic activity.

Dlk (also termed ZIP kinase) is a novel serine/threonine kinase with a unique C-terminal domain that is rich in arginine and contains three putative NLS motifs and a functional lecuine zipper. Dlk is indeed localized in the nucleus where it shows a speckled distribution. To elucidate the biological functions of Dlk, we wanted to identify the signals relevant for nuclear transport and further the nuclear structures which Dlk binds to. Expression of various deletion and point mutations of Dlk as GFP fusion proteins revealed that the leucine zipper is required for association with speckles and the most C-terminal NLS is necessary and sufficient for nuclear transport. Interestingly, a C-terminal deletion mutant defective for nuclear transport exhibited a pronounced colocalization with actin filaments and, even more strikingly, was a very potent inducer of apoptosis. This apoptotic activity was abrogated, however, when this mutant was retargeted to the nucleus via a heterologous NLS from large T, indicating that Dlk only exerts an apoptotic activity in the cytoplasm. To identify the speckle like structures to which Dlk binds we performed immunofluorescence analyses with antibodies directed against representative marker proteins of replication, transcription, or splicing centers. None of these marker proteins revealed a colocalization with Dlk. Instead, we found a partial colocalization with PML bodies which seem to play a key role in regulation of apoptosis. Taken together, these data strongly suggest a functional role for Dlk in control of cell survival which is dependent on its subcellular localization.