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Biomedical subjects

M D Jacobson

Publications and source records attributed to M D Jacobson.

At least 37 records · Page 2Linked to original sources

Reactive oxygen species and programmed cell death.

Bcl-2 is a proto-oncoprotein with apparently one function--to suppress programmed cell death (PCD)--yet how it does so remains a mystery. Several authors have proposed that Bcl-2 is an antioxidant that suppresses the formation or action of reactive oxygen species (ROS) and in this way inhibits PCD. However, three recent papers indicate that ROS are not required for PCD and that Bcl-2 can protect against cell death even under conditions where ROS are unlikely to be produced.

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Programmed cell death and Bcl-2 protection in very low oxygen.

Programmed cell death (PCD) is a fundamental feature of animal cells, but the mechanism remains unknown. Similarly, the Bcl-2 oncoprotein can suppress PCD in a variety of cell types and circumstances, but it is not known how it does so. It has been suggested that PCD involves the generation of reactive oxygen species (ROS) and that Bcl-2 protects against PCD by inhibiting the generation or action of ROS. To determine whether ROS are required for PCD, we cultured cells in a near-anaerobic atmosphere where the generation of ROS would be expected not to occur, or at least to be greatly reduced. We find that these conditions inhibit PCD induced by ROS-generating agents but do not inhibit PCD induced by other means. Furthermore, we show that Bcl-2 can protect cells from PCD in these anaerobic conditions. These results suggest that ROS are not required for PCD, and that Bcl-2 protects against PCD in ways that do not depend on the inhibition of ROS production or activity.

Alkaloids↗

Programmed cell death and the control of cell survival.

We draw the following tentative conclusions from our studies on programmed cell death (PCD): (i) the amount of normal cell death in mammalian development is still underestimated; (ii) most mammalian cells constitutively express the proteins required to undergo PCD; (iii) the death programme operates by default when a mammalian cell is deprived of signals from other cells; (iv) many normal cell deaths may occur because cells fail to obtain the extracellular signals they need to suppress the death programme; and (v) neither the nucleus nor mitochondrial respiration is required for PCD (or Bcl-2 protection from PCD), raising the possibility that the death programme, like mitosis, is orchestrated by a cytosolic regulator that acts on multiple organelles in parallel.

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Programmed cell death and Bcl-2 protection in the absence of a nucleus.

The molecular basis of programmed cell death (PCD) is unknown. An important clue is provided by the Bcl-2 protein, which can protect many cell types from PCD, although it is not known where or how it acts. Nuclear condensation, DNA fragmentation and a requirement for new RNA and protein synthesis are often considered hallmarks of PCD. We show here, however, that anucleate cytoplasts can undergo PCD and that Bcl-2 and extracellular survival signals can protect them, indicating that, in some cases at least, the nucleus is not required for PCD or for Bcl-2 or survival factor protection. We propose that PCD, like the cell cycle, is orchestrated by a cytoplasmic regulator that has multiple intracellular targets.

Alkaloids↗

Apoptosis. Breaking the ICE.

Structural and functional similarities have been discovered between two mammalian proteins. Bcl-2 ang interleukin 1 beta-converting enzyme, and proteins encoded by nematode cell-death genes.

Animals↗

Programmed cell death and the control of cell survival: lessons from the nervous system.

During the development of the vertebrate nervous system, up to 50 percent or more of many types of neurons normally die soon after they form synaptic connections with their target cells. This massive cell death is thought to reflect the failure of these neurons to obtain adequate amounts of specific neurotrophic factors that are produced by the target cells and that are required for the neurons to survive. This neurotrophic strategy for the regulation of neuronal numbers may be only one example of a general mechanism that helps to regulate the numbers of many other vertebrate cell types, which also require signals from other cells to survive. These survival signals seem to act by suppressing an intrinsic cell suicide program, the protein components of which are apparently expressed constitutively in most cell types.

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Does oligodendrocyte survival depend on axons?

BACKGROUND: We have shown previously that oligodendrocytes and their precursors require signals from other cells in order to survive in culture. In addition, we have shown that about 50% of the oligodendrocytes produced in the developing rat optic nerve normally die, apparently in a competition for the limiting amounts of survival factors. We have hypothesized that axons may control the levels of such oligodendrocyte survival factors and that the competition-dependent death of oligodendrocytes serves to match their numbers to the number of axons that they myelinate. Here we test one prediction of this hypothesis - that the survival of developing oligodendrocytes depends on axons. RESULTS: We show that oligodendrocyte death occurs selectively in transected nerves in which the axons degenerate. This cell death is prevented by the delivery of exogenous ciliary neurotrophic factor (CNTF) or insulin-like growth factor I (IGF-1), both of which have been shown to promote oligodendrocyte survival in vitro. We also show that purified neurons promote the survival of purified oligodendrocytes in vitro. CONCLUSION: These results strongly suggest that oligodendrocyte survival depends upon the presence of axons; they also support the hypothesis that a competition for axon-dependent survival signals normally helps adjust the number of oligodendrocytes to the number of axons that require myelination. The identities of these signals remain to be determined.

Journal Article↗

Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA.

When the mammalian proto-oncogene bcl-2 is overexpressed it can protect various types of cells both from normal and from experimentally induced apoptosis, but the molecular mechanisms involved are unknown. Although the Bcl-2 protein is membrane-associated, its subcellular location is controversial: two studies have suggested that it is mainly associated with the nuclear envelope and endoplasmic reticulum, whereas another study has suggested that it is mainly located in the inner mitochondrial membrane. The latter study has suggested that Bcl-2 might protect cells from apoptosis by altering mitochondrial function and that mitochondria may be involved in apoptosis. Here we report that human mutant cell lines that lack mitochondrial DNA (mtDNA), and therefore do not have a functional respiratory chain, can still be induced to die by apoptosis, and that they can be protected from apoptosis by the overexpression of bcl-2, suggesting that neither apoptosis nor the protective effect of bcl-2 depends on mitochondrial respiration. We also show that the Bcl-2 protein in overexpressing cells is associated with the nuclear envelope and endoplasmic reticulum, as well as with mitochondria.

Alkaloids↗

Architecture of selected muscles of the arm and forearm: anatomy and implications for tendon transfer.

The architectural features of twenty-one different forearm muscles (n = 154 total muscles) were studied. Muscles included the extensor digitorum communis to the index, middle, ring, and small fingers, the extensor digit quinti, the extensor indicis proprius, the extensor pollicis longus, the flexor digitorum superficialis, the flexor digitorum profundus, the flexor pollicis longus, the pronator quadratus, the palmaris longus, the pronator teres, and the brachioradialis. Muscle length, mass, fiber pennation angle, fiber length, and sarcomere length were determined with the use of laser diffraction techniques. From these values, physiologic cross-sectional area and fiber length/muscle length ratio were calculated. The individual digital extensor muscles were found to be relatively similar in architectural structure. Similarly, the deep and superficial digital flexors were very similar architecturally, with the exception of the small finger flexor digitorum superficialis, which was much smaller and shorter than the rest of the digital flexors. The brachioradialis and the pronator teres had dramatically different architectural properties. While the masses of the two muscles were nearly identical, the muscles had significantly different predicted contractile properties based on their different fiber arrangement. The brachioradialis, with its long fibers arranged at a small pennation angle, had a physiologic cross-sectional area that was only one third that of the pronator teres, with its short fibers that were more highly pennated. Using these architectural data and the statistical method of discriminant analysis, we provide additional information that might be useful in the selection of potential donor muscles to restore thumb flexion, thumb extension, finger extension, and finger flexion.

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Architectural design of the human intrinsic hand muscles.

The architectural features of twenty different muscles (18 intrinsics and 2 thumb extrinsics, n = 180 total muscles) were studied. Muscle length, mass, fiber pennation angle, fiber length, and sarcomere length were determined. From these values, physiologic cross-sectional area and fiber length/muscle length ratio were calculated. Intrinsic muscle lengths were relatively similar to one another, which we interpreted as representing a space constraint within the hand. However, several specialized architectural designs were observed: lumbrical muscles had an extremely high fiber length/muscle length ratio, implying a design toward high excursion. The first dorsal interosseous and adductor pollicis had physiologic cross-sectional areas comparable to those of extrinsic muscles and much greater than those of the other intrinsic muscles. The interosseous muscles had relatively high physiologic cross-sectional areas with low fiber length/muscle length ratios, suggesting their adaptation for high force production and low excursion. Taken together, these observations illustrate the underlying structural basis for the functional capacities of the intrinsic muscles.

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Muscarinic receptors and hydrolysis of inositol phospholipids in rat cerebral cortex and parotid gland.

Exposure of rat brain or parotid gland slices to muscarinic receptor agonists stimulates a phospholipase C that degrades inositol phospholipids. When tissue slices were labelled in vitro with [3H]inositol, this response could be monitored by measuring the formation of [3H]inositol phosphates. Accumulation of inositol 1,4-biphosphate in stimulated brain slices suggests that polyphosphonositides are the primary targets for phospholipase C activity. Li+ (10 mM) in the medium completely blocked the hydrolysis of inositol 1-phosphate, partially inhibited inositol 1,4-bisphosphate hydrolysis, but had no effect on the hydrolysis of inositol 1,4,5-trisphosphate by endogenous phosphatases. Muscarinic receptor pharmacology was studied by measuring the accumulation of [3H]inositol 1-phosphate in the presence of 10 mM Li+. In experiments on brain slices, the response to carbachol was antagonised by atropine with an affinity constant of approximately 8.79 +/- 0.12. Dose-response curves to several muscarinic agonists were constructed using brain and parotid gland slices. The results are consistent with relatively direct coupling of low-affinity muscarinic receptors to inositol phospholipid breakdown in brain slices; full agonists were relatively more potent in the parotid gland compared with the brain. Explanations for these differences are suggested.

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