Biomedical subjects

Susanna Ekholm-Reed

Publications and source records attributed to Susanna Ekholm-Reed.

3 recordsLinked to original sources

PubMed2004

Deregulation of cyclin E in human cells interferes with prereplication complex assembly.

Deregulation of cyclin E expression has been associated with a broad spectrum of human malignancies. Analysis of DNA replication in cells constitutively expressing cyclin E at levels similar to those observed in a subset of tumor-derived cell lines indicates that initiation of replication and possibly fork movement are severely impaired. Such cells show a specific defect in loading of initiator proteins Mcm4, Mcm7, and to a lesser degree, Mcm2 onto chromatin during telophase and early G1 when Mcm2-7 are normally recruited to license origins of replication. Because minichromosome maintenance complex proteins are thought to function as a heterohexamer, loading of Mcm2-, Mcm4-, and Mcm7-depleted complexes is likely to underlie the S phase defects observed in cyclin E-deregulated cells, consistent with a role for minichromosome maintenance complex proteins in initiation of replication and fork movement. Cyclin E-mediated impairment of DNA replication provides a potential mechanism for chromosome instability observed as a consequence of cyclin E deregulation.

Breast Neoplasms↗

PubMed2004

Mutation of hCDC4 leads to cell cycle deregulation of cyclin E in cancer.

hCDC4, the gene that encodes the F-box protein responsible for targeting cyclin E for ubiquitin-mediated proteolysis, has been found to be mutated in a number of primary cancers and cancer-derived cell lines. We have observed that functional inactivation of hCDC4 does not necessarily correlate with elevated levels of cyclin E in tumors. Here we show, however, that hCDC4 mutation in primary tumors correlates strongly with loss of cell cycle regulation of cyclin E. Similarly, a breast carcinoma-derived cell line mutated for hCDC4 exhibits cell cycle deregulation of cyclin E, but periodic expression is restored by reintroducing hCDC4 via retroviral transduction. Conversely, small interfering RNA-mediated silencing of hCdc4 deregulates cyclin E with respect to the cell cycle. These results indicate that hCdc4 function is an absolute prerequisite for cell cycle regulation of cyclin E levels, and loss of hCdc4 function is sufficient to deregulate cyclin E.

Breast Neoplasms↗

PubMed2003

Abnormal expression pattern of cyclin E in tumour cells.

The expression pattern of cyclin E during the cell cycle was studied in normal and tumour cells in culture and in tumour biopsies. This pattern was found to be abnormal in tumour cells. A triple immunostaining protocol, digital microscopy and image analysis were used to find the position of the individual cells in the cell cycle and to measure the nuclear cyclin E levels. In normal cells, the number of cyclin E-positive cells decreased rapidly when the cells entered the S-phase. In the tumour cell lines, cyclin E was not downregulated in early S-phase, as in normal cells. Instead the number of cyclin E-positive cells remained high throughout S-phase, and the cyclin E staining intensity per cell often increased during S-phase. In about half of the analysed tumour cell lines, many cells stained positive for cyclin E even in the G(2)-phase. This abnormal expression over the cell cycle of cyclin E was also found in tumour biopsies from cervical, breast and prostatic carcinomas, even though it varied greatly between individual tumours. In some tumours, the expression pattern of cyclin E was similar to that of normal cells in culture, whereas in others high cyclin E levels could be seen in S-phase cells, as in the transformed cell lines. A high percentage of cells expressing cyclin E during S- or G(2)-phase was found to be related to poor outcome (p < 0.025) in a small group of cervical carcinoma patients (n = 12).

Biomarkers, Tumor↗