Biomedical subjects

Sabine Mai

Publications and source records attributed to Sabine Mai.

23 records · Page 2Linked to original sources

PubMed2003

c-Myc-induced genomic instability.

c-myc is one of a small family of proto-oncogenes that do not require mutation to contribute to neoplastic transformation. Instead, the deregulated expression of the oncoprotein at even modest levels is sufficient to initiate this process. The transforming activity of c-Myc is generally thought to lie in its ability to modulate the expression of a series of genes, among them certain proliferation-promoting genes. In reality, c-Myc is a multifunctional protein that also affects the stability of the genome. In this review, we summarize the growing evidence that deregulated c-myc expression generates genomic instability by initiating gene amplification (both intra- and extra-chromosomally), gene rearrangements, and karyotypic instability. Cancer is a disease of impaired genomic stability, to which c-Myc contributes during its initiation and progression through the induction of genomic instability in critical genes. Myc thus acts as a structural modifier of the genome and as a promoter of neoplastic transformation.

Cell Transformation, Neoplastic↗

PubMed2002

c-MYC overexpression in Ba/F3 cells simultaneously elicits genomic instability and apoptosis.

Overexpression of c-Myc in tumors is usually associated with cell proliferation and increased susceptibility to apoptosis. Concomitantly, c-Myc contributes to tumorigenesis by its ability to destabilize the cellular genome. Here, we examined whether c-Myc induces genomic instability and apoptosis in c-Myc-activated cells. Wild-type Myc (wt-Myc) and two mutated Myc myc box II proteins (mt-Myc) were overexpressed in IL3-dependent murine Ba/F3 cells. As expected, wt-Myc triggered apoptosis in absence of IL3. Standard karyotyping, spectral karyotyping, and fluorescent in situ hybridization (FISH) were performed before and after c-Myc activation. Structural and numerical genomic instability was detected 48 h after wt-Myc activation and included gene amplification, the formation of extrachromosomal elements (EEs), chromosome breakage, deletions, increased aneuploidy, and polyploidization. Interestingly, some cells simultaneously displayed genomic instability and apoptosis. Both wt- and mt-Myc proteins were equally potent promoters of genomic instability. However, only wt-Myc simultaneously induced genomic instability and apoptosis. Mt-Myc proteins failed to induce apoptosis, thereby generating a strong imbalance towards the survival of genomically unstable cells.

Aneuploidy↗

PubMed2002

Technique and first clinical results of robot-assisted total knee replacement.

Total knee replacement (TKR) is a common procedure for treatment of severe gonarthrosis, but the outcome may be unsatisfactory due to primary malalignment of the prosthetic components. In order to improve precision and accuracy of this surgical procedure, a commercial robotic surgical system (CASPAR) has been adapted to assist the surgeon in the preoperative planning and intraoperative execution of TKR. So far, 70 patients with idiopathic gonarthrosis were successfully treated with a robot-assisted technique in our institution. No major adverse events related to the use of the robotic system have been observed. The mean difference between preoperatively planned and postoperatively achieved tibiofemoral alignment was 0.8 degrees (0-4.1 degrees ) in the robotic group vs. 2.6 degrees (0-7 degrees ) in a manually operated historical control group of 50 patients. A clear advantage of robot-assisted TKR seems to be the ability to execute a highly precise preoperative plan based on computed tomography (CT) scans. Due to better alignment of the prosthetic components and improved bone-implant fit, implant loosening is anticipated to be diminished which may be most evident in non-cemented prostheses. Current disadvantages such as the need for placement of fiducial markers, increased operating times and higher overall costs have to be resolved in the future.

Aged↗

PubMed2002

The impact of p53 loss on murine plasmacytoma development.

Mouse plasmacytomas (PCTs) are characterized by c-myc-activating translocations that juxtapose c-myc on chromosome 15 onto one of the immunoglobulin loci (IgH on chromosome 12, IgK on chromosome 6, or IgA on chromosome 16). To assess the impact of p53 loss on PCT genesis, we induced PCTs in p53-deficient BALB/cRb6.15 mouse strains. We show that p53 loss accelerates tumor development and causes a shift in the typical translocation patterns. PCTs that carry variant T(6;15) translocations become as frequent as those with typical T(12;15) translocations (41.66%). In addition, in the absence of p53, the number of translocation-negative PCTs increases from less than 1% to 16.66%. It is noteworthy that neither the shortened latency periods nor the shift in translocation patterns had an impact on the incidence of PCT development. The 42.2% incidence in N3p53-/- mice is similar to the percentages recorded in groups of conventional BALB/cAn mice. The possible mechanisms underlying the accelerated tumorigenesis and the shift in translocation patterns are discussed.

Animals↗

PubMedDate not supplied

c-Myc-induced extrachromosomal elements carry active chromatin.

Murine Pre-B lymphocytes with experimentally activated MycER show both chromosomal and extrachromosomal gene amplification. In this report, we have elucidated the size, structure, and functional components of c-Myc-induced extrachromosomal elements (EEs). Scanning electron microscopy revealed that EEs isolated from MycER-activated Pre-B+ cells are an average of 10 times larger than EEs isolated from non-MycER-activated control Pre-B- cells. We demonstrate that these large c-Myc-induced EEs are associated with histone proteins, whereas EEs of non-MycER-activated Pre B- cells are not. Immunohistochemistry and Western blot analyses using pan-histone-specific, histone H3 phosphorylation-specific, and histone H4 acetylation-specific antibodies indicate that a significant proportion of EEs analyzed from MycER-activated cells harbors transcriptionally competent and/or active chromatin. Moreover, these large, c-Myc-induced EEs carry genes. Whereas the total genetic make-up of these c-Myc-induced EEs is unknown, we found that 30.2% of them contain the dihydrofolate reductase (DHFR) gene, whereas cyclin C (CCNC) was absent. In addition, 50% of these c-Myc-activated Pre-B+ EEs incorporated bromodeoxyuridine (BrdU), identifying them as genetic structures that self-propagate. In contrast, EEs isolated from non-Myc-activated cells neither carry the DHFR gene nor incorporate BrdU, suggesting that c-Myc deregulation generates a new class of EEs.

Animals↗