Biomedical subjects

E A Harrington

Publications and source records attributed to E A Harrington.

6 recordsLinked to original sources

PubMed2000

ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation.

We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm-deficient (Atm-/-) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hind-paw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm-/- mice analyzed in most laboratories. Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm-/- mice to determine whether there was evidence of neuronal abnormality. We found a significant increase in the number of lysosomes in Atm-/- mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, we found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells. The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum. These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an increase in lysosomal numbers.

Animals↗

PubMed1998

pRB plays an essential role in cell cycle arrest induced by DNA damage.

To maintain genome stability, cells with damaged DNA must arrest to allow repair of mutations before replication. Although several key components required to elicit this arrest have been discovered, much of the pathway remains elusive. Here we report that pRB acts as a central mediator of the proliferative block induced by a diverse range of DNA damaging stimuli. Rb-/- mouse embryo fibroblasts are defective in arrest after gamma-irradiation, UV irradiation, and treatment with a variety of chemotherapeutic drugs. In contrast, the pRB related proteins p107 and p130 do not play an essential part in the DNA damage response. pRB is required specifically for the G1/S phase checkpoint induced by gamma-irradiation. Despite a defect in G1/S phase arrest, levels of p53 and p21 are increased normally in Rb-/- cells in response to gamma-irradiation. These results lead us to propose a model in which pRB acts as an essential downstream target of the DNA damage-induced arrest pathway. The ability of pRB to prevent replication of damaged DNA is likely to inhibit the propagation of carcinogenic mutations and may therefore contribute to its role as a tumor suppressor. Furthermore, because many cancer therapies act by damaging DNA, these findings also have implications for the treatment of tumors in which pRB is inactivated.

Animals↗

PubMed1995

Induction of apoptosis by the Bcl-2 homologue Bak.

Cells are eliminated in a variety of physiological settings by apoptosis, a genetically encoded process of cellular suicide. Apoptosis comprises an intrinsic cellular defence against tumorigenesis, which, when suppressed, may contribute to the development of malignancies. The bcl-2 oncogene, which is activated in follicular lymphomas, functions as a potent suppressor of apoptosis under diverse conditions. Here we describe the complementary DNA cloning and functional analysis of a new Bcl-2 homologue, Bak, which promotes cell death and counteracts the protection from apoptosis provided by Bcl-2. Moreover, enforced expression of Bak induces rapid and extensive apoptosis of serum-deprived fibroblasts. This raises the possibility that Bak is directly involved in activating the cell death machinery.

Amino Acid Sequence↗

PubMed1994

c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines.

We have investigated the mechanism by which deregulated expression of c-Myc induces death by apoptosis in serum-deprived fibroblasts. We demonstrate that Myc-induced apoptosis in low serum is inhibited by a restricted group of cytokines, principally the insulin-like growth factors and PDGF. Cytokine-mediated protection from apoptosis is not linked to the cytokines' abilities to promote growth. Protection from apoptosis is evident in the post-commitment (mitogen-independent) S/G2/M phases of the cell cycle and also in cells that are profoundly blocked in cell cycle progression by drugs. Moreover, IGF-I inhibition of apoptosis occurs in the absence of protein synthesis, and so does not require immediate early gene expression. We conclude that c-Myc-induced apoptosis does not result from a conflict of growth signals but appears to be a normal physiological aspect of c-Myc function whose execution is regulated by the availability of survival factors. We discuss the possible implications of these findings for models of mammalian cell growth in vivo.

Animals↗

PubMed1994

Oncogenes and cell death.

Several recent studies have implicated oncogenes and tumour suppressor genes in the regulation of programmed cell death (apoptosis). Lesions in the cell death pathway appear to be important in both carcinogenesis and the evolution of drug resistance in tumours. They include deregulated expression of genes such as bcl-2, loss of p53, and autocrine activation of anti-apoptotic signal transduction pathways. Paradoxically, a number of dominant oncogenes appear to act as potent inducers of apoptosis. This suggests that the pathways of cell proliferation and cell death may be tightly coupled, an idea that may have dramatic implications for models of oncogene co-operation and carcinogenesis.

Animals↗

PubMed1992

Cooperative interaction between c-myc and bcl-2 proto-oncogenes.

The bcl-2 proto-oncogene is activated by translocation in a variety of B-lymphoid tumours and synergizes with the c-myc oncogene in tumour progression. The mechanism of synergy is unclear but bcl-2 expression inhibits apoptosis, a property presumably pertinent to its proto-oncogenic mode of action. We have shown that the c-myc gene is a potent inducer of apoptosis, in addition to its established role in mitogenesis. Here we show that expression of the bcl-2 protein, Bcl-2, specifically abrogates c-myc-induced apoptosis without affecting the c-myc mitogenic function. This provides a novel mechanism for oncogene cooperation, of potential importance both in carcinogenesis and in the evolution of drug resistance in tumours.

Apoptosis↗