The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Hypothalamic Integration: Organization of the Paraventricular and Supraoptic Nuclei

Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

Physiology of local renin-angiotensin systems.

Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat

Renin-angiotensin system: biochemistry and mechanisms of action.

Because of the increasing use of morphine anesthesia for open-heart surgery and the known ability of the drug to inhibit ACTH release, we have studied the effect of morphine anesthesia on plasma cortisol and growth hormone response to major surgery. In patients receiving 1 mg/kg morphine anesthesia the normal rise in plasma cortisol in response to major abdominal surgery was suppressed. This was also true in patients receiving 4 mg/kg morphine as anesthesia for open-heart surgery. In the latter group the normal rise in serum growth hormone was suppressed as well. This suppression of cortisol and growth hormone response during morphine anesthesia caused no clinically observable ill effect and could be reversed with ACTH.

Morphine Anesthesia Blocks Cortisol and Growth Hormone Response to Surgical Stress in Humans

Tumors from patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been found to contain large amounts of the antidiuretic hormone vasopressin. A lung tumor from a patient with hyponatremia most likely due to SIADH was removed at surgery and found to contain 23.5 mU vasopressin/g wet weight by radioimmunoassay Slices of this tumor were incubated with phenylalanine-(3)H. Arginine vasopressin-(3)H was purified from the incubate by Sephadex G-25 column chromatography in two different systems, performic acid oxidation, and gradient elution column chromatography with diethylaminoethyl Sephadex. As oxidation of vasopressin results in drastic conformational change with breaking of the ring of the cyclic polypeptide and addition of two cysteic acid residues per molecule, the radioactive material which eluted coincident with vasopressin both before and after this procedure was considered to be arginine vasopressin-(3)H. To our knowledge this is the first demonstration of in vitro biosynthesis of vasopressin by a tumor from a patient with SIADH.Ultrastructurally, the bronchogenic carcinoma was composed of small undifferentiated and granulated cells. The granulated neoplastic cells had well developed organelles (endoplasmic reticulum, free ribosomes) concerned with protein synthesis. Secretion granules present in the tumor cells were small, surrounded by a limiting membrane, and resembled those reported in polypeptide hormone-secreting cells.

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Biosynthesis of Vasopressin In Vitro and Ultrastructure of a Bronchogenic Carcinoma: PATIENT WITH THE SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE

Enhancement of attention in man with ACTH/MSH 4-10.

Eleven healthy male volunteers were infused with MSH/ACTH 4–10 and a control solution in a completely crossed and balanced procedure. Perception, attention and memory were tested as were heart rate and cephalic pulse amplitude in response to changes in the environment. Treatment of subjects with MSH/ACTH 4–10 raised their perceptual threshold for detection of simple stimuli and facilitated perceptual integration of patterned information. Administration of the heptapeptide improved the subjects' ability to discriminate tests of relevant from irrelevant information and augmented the heart–rate deceleratory response during presentation of novel stimuli. It was speculated that MSH/ACTH 4–10 has a predominant influence on attentional processes and that it may be uniquely coded for attentional/perceptual functioning.

Jack M. George

Papers

Morphine Anesthesia Blocks Cortisol and Growth Hormone Response to Surgical Stress in Humans

Biosynthesis of Vasopressin In Vitro and Ultrastructure of a Bronchogenic Carcinoma: PATIENT WITH THE SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE

Enhancement of attention in man with ACTH/MSH 4-10.

MSH/ACTH 4-10 Influences Behavioral and Physiological Measures of Attention

The syndrome of primary aldosteronism.