It has now been nearly 15 years since the immediate early gene, c-fos, and its protein product, Fos, were introduced as tools for determining activity changes within neurones of the nervous system. In the ensuing years, this approach was applied to neuroendocrine study with success. With it have come advances in our understanding of which neuroendocrine neurones respond to various stimuli and how other central nervous system components interact with neuroendocrine neurones. Use of combined tract-tracing approaches, as well as double-labelling for Fos and transmitter markers, have added to characterization of neuroendocrine circuits. The delineation of the signal transduction cascades that induce Fos expression has led to establishment of the relationship between neurone firing and Fos expression. Importantly, we can now appreciate that Fos expression is often, but not always, associated with increased neuronal firing and vice versa. There are remaining gaps in our understanding of Fos in the nervous system. To date, knowledge of what Fos does after it is expressed is still limited. The transience of Fos expression after stimulation (especially if the stimulus is persistent) complicates design of experiments to assess the function of Fos and makes Fos of little value as a marker for long-term changes in neurone activity. In this regard, alternative approaches must be sought. Useful alternative approaches employed to date to monitor neuronal changes in activity include examination of (i) signal transduction intermediates (e.g. phosphorylated CREB); (ii) transcriptional/translational intermediates (e.g. heteronuclear RNA, messenger RNA (mRNA), prohormones); and (iii) receptor translocation. Another capitalizes on the fact that many neuroendocrine systems show striking stimulus-transcription coupling in the regulation of their transmitter or its synthetic enzymes. Together, as we move into the 21st Century, the use of multiple approaches to study activity within neuroendocrine systems will further our understanding of these important systems. The introduction of Fos to the study of neuroendocrine systemsIn the late 1980s the discovery that neurones transiently expressed the immediate early gene c-fos when stimulated (1) added a new dimension to the concept of functional neuroanatomy. For the first time, scientists could examine networks of neurones within multiple sites in the nervous system and identify specific neurones that were 'activated' by a stimulus. For the neuroendocrine systems, the availability of this approach provided critical information concerning how, when and where stimuli to neuroendocrine systems were processed. The fact that the protein expressed by the c-fos gene, Fos, was nuclear and could be detected immunocytochemically further permitted double-labelling of activated neurones for identity of their transmitter (2), a feature essential when the neuroendocrine neurones are diffusely organized. This feature is illustrated in Fig. 1A which depicts (i) luteinizing hormone-releasing hormone...
The ability of cancer cells to migrate is strongly correlated with malignant progression and metastasis. Survival signals that suppress apoptosis have also been linked to increased cell motility. We previously reported that suppression of protein kinase Cd (PKCd) provided survival signals in a rat fibroblast model system. These studies have been extended to human breast cancer cells with differential cell motilities and PKCd levels. BT-549 cells, which lack detectable expression of PKCd, migrate very efficiently, whereas MCF-7 cells, which express high levels of PKCd, migrate very poorly. Ectopic expression of PKCd suppressed cell migration in the BT-549 cells, and downregulation of PKCd enhanced cell migration in the MCF-7 cells. Downregulation of PKCd in the MCF-7 cells also led to increased secretion of the matrix metalloprotease MMP-9. The migration of mouse embryo fibroblasts (MEFs) from wild type and PKCd knockout mice was also examined and MEFs from PKCd knockout mice had a five-fold increase in cell migration relative to the wild-type MEFs. These data provide evidence that PKCd suppresses cell migration in both human breast cancer cells and in primary mouse fibroblasts, and indicate that the loss of PKCd in human cancers could contribute to both cell survival and metastasis.
We examined how the experience of a threatening stimulus alters subsequent behavior in a situation where the immediate threat is absent. A small huddle of 12-day-old rats was exposed to a potentially infanticidal adult male rat for 5 min. During male exposure, pups were significantly more immobile than control pups. Thirty, 60, and 180 min after male exposure, the pups were isolated for 5 min from litter and dam in an unfamiliar environment. When isolated, pups that had been previously exposed to the male emitted significantly fewer ultrasonic vocalizations than controls, but did not differ in immobility. Low levels of vocalization were apparent 30 and 60 min after male exposure and were not evident at 180 min. The pups seemed to have adjusted their behavior to a potential male threat in a different context for a limited period of time. ß
Phosphatidic acid (PA), the primary metabolite of the phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine, has been shown to act as a tumor promoting second messenger in many cancer cell lines. A key target of PA is the mammalian target of rapamycin (mTOR), a serine-threonine kinase that has been widely implicated in cancer cell survival signals. In agreement with its ability to relay survival signals, it has been reported that both PLD and mTOR are required for the stabilization of the p53 E3 ubiquitin ligase human double minute 2 (HDM2) protein. Thus, by stabilizing HDM2, PLD and mTOR are able to counter the pro-apoptotic signaling mediated by p53 and promote survival. mTOR exists in at least two distinct complexesmTORC1 and mTORC2 -that are both dependent on PLD-generated PA. Although PLD and its metabolite PA are clearly implicated in the transduction of survival signals to mTOR, it is not yet apparent which of the two mTOR complexes is critical for the stabilization of HDM2. We report here that the PLD/mTOR-dependent stabilization of HDM2 involves mTORC2 and the AGC family kinase serum-and glucocorticoid-inducible kinase 1 (SGK1). This study reveals that mTORC2 is a critical target of PLD-mediated survival signals and identifies SGK1 as a downstream target of mTORC2 for the stabilization of HDM2.
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