Non-nuclear Pathways Research Articles

Estrogen Receptor-Positive Breast Cancer: Exploiting Signaling Pathways Implicated in Endocrine Resistance.

The foundational strategy for treating hormone receptor-positive, human epidermal growth receptor 2-negative, advanced breast cancer includes the use of endocrine therapy either alone or in combination with targeted agents. The use of combination therapy aims to downregulate cell-signaling pathways with the intent of minimizing cellular "crosstalk," which can otherwise result in continued tumorigenesis or progression through redundant pathways. This review provides the clinician with the molecular rationale and clinical evidence for these treatments and refers to evidence-based guidelines to inform the decision-making process.

Estradiol-tethered micropatterned surfaces for the study of estrogenic non-genomic pathways.

Besides its well-known hormonal effects initiated in the nucleus, estradiol (E2) also activates non-nuclear pathways through interactions with receptors located on the cell plasma membrane. Micropatterned substrates consisting of gold dots bearing tethered E2 distributed on a cell-adhesive substrate were prepared and shown to trigger specifically E2 non-genomic effects in cells grown on the substrates.

Sex steroid hormone receptors, their ligands, and nuclear and non-nuclear pathways

The ability of a cell to respond to a particular hormone depends on the presence of specific receptors for those hormones. Once the hormone has bound to its receptor, and following structural and biochemical modifications to the receptor, it separates from cytoplasmic chaperone proteins, thereby exposing the nuclear localization sequences that result in the activation of the receptor and initiation of the biological actions of the hormone on the target cell. In addition, recent work has demonstrated new pathways of steroid signaling through orphan and cell surface receptors that contribute to more rapid, “non-nuclear” or non-transcriptional effects of steroid hormones, often involving G-protein-mediated pathways. This review will summarize some of these studies for estrogens, androgens and progestins.

The Roles of MAPKs in Rabbit Nucleus Pulposus Cell Apoptosis Induced by High Osmolality

Earlier work has suggested that the p38 MAPK, JNK1/2 and ERK1/2 signal pathway existed in nucleus pulposus cells and the cell growth, differentiation and apoptosis were regulated by them. Because osmotic fluctuations are inevitable in the physicochemical environment of intervertebral disc cells, high osmolality could activate p38 MAPK, JNK1/2 and ERK1/2 signal pathway. The effects of high osmolality on the catabolic program and proliferation of nucleus pulposus cells are still not clear. To explore the possible roles of MAPKs in rabbit nucleus pulposus cell apoptosis induced by high osmolality. Rabbit nucleus pulposus cells were cultured and divided into different group at random. The cells were pretreated with inhibitor for p38 MAPK, JNK1/2 and ERK1/2 signal pathway respectively. In next step, the cells were cultured in different osmolality environment for different time at 37°C in 5% carbon dioxide incubator. After treatments, ratio of apoptosis was measured by flow cytometry, and western blotting was performed to quantify the expression of the activated forms of p38 MAPK, JNK1/2 and ERK1/2. Furthermore, immunofluorescence analysis with confocal microscopy was performed to confirm the hyperosmolality effects on activation of p38 MAPK, JNK1/2 and ERK1/2 signal pathways in nucleus pulposus cells. Our results show that in 500 and 600 mOsm/kg medium, rabbit nucleus pulposus cell apoptosis increased, and a persistent phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 proteins were observed. In the same condition, the apoptotic cells death remarkably decreased when the p38 MAPK and JNK1/2 signal pathways were blocked by their inhibitors SB203580, SP600125 repectively. On the other side, the apoptotic cells death rate reraised greatly when the ERK1/2 signal pathways were blocked by its inhibitor PD98059. High osmolality activated p38MAPK, JNK1/2 and ERK1/2 in rabbit nucleus pulposus cell, and the activated p38 MAPK and JNK1/2 induced cell apoptosis, on the contrary, the activated ERK1/2 made the cell survived.

Neuroprotection Against Transient Focal Cerebral Ischemia and Oxygen–Glucose Deprivation by Interference with GluR6-PSD95 Protein Interaction

Previous studies have shown that KA receptor subunit GluR6 mediated c-Jun N-terminal protein kinase (JNK) signaling is involved in global ischemia injury. Our present study indicates that focal ischemic brain insult on rat middle cerebral artery occlusion (MACo) model enhances the assembly of the GluR6-PSD95-MLK3 module and facilitates the phosphorylation of JNK. Most importantly, a peptide containing the TAT protein transduction sequence, Tat-GluR6-9c, can perturb the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK7/4 and JNK. As result, the inhibition of JNK activation caused by Tat-GluR6-9c diminishes the phosphorylation of the transcription factor c-Jun, down-regulates FasL expression and attenuates bax translocation, release of cytochrome c and the activation of caspase-3. Furthermore, MCAo induced infract volume is reduced by intracerebroventricular injection of Tat-Glur6-9c. Oxygen-glucose-deprivation (OGD) cultured cortical neuronal cell also shows an improved cell viability by application of Tat-GluR6-9c. Taken together, our findings strongly suggest that GluR6-PSD95-MLK3 signaling module mediated activation of nuclear and non-nuclear pathways of JNK activation are involved in focal ischemia injury and OGD. Tat-GluR6-9c, the peptide we constructed, gives a new insight into the therapy for ischemic stroke.

Neuroprotection of preconditioning against ischemic brain injury in rat hippocampus through inhibition of the assembly of GluR6—PSD95—mixed lineage kinase 3 signaling module via nuclear and non-nuclear pathways

Our previous studies showed that the assembly of the GluR6–PSD95–mixed lineage kinase 3 (MLK3) signaling module played an important role in rat ischemic brain injury. In this study, we aimed to elucidate whether ischemic preconditioning could downregulate the assembly of the GluR6–PSD95–MLK3 signaling module and suppress the activation of MLK3, MKK4/7, and c-Jun N-terminal kinase (JNK). As a result, ischemic preconditioning could not only inhibit the assembly of the GluR6–PSD95–MLK3 signaling module, diminish the phosphorylation of the transcription factor c-Jun, downregulate Fas ligand expression, attenuate the phosphorylation of 14-3-3 and Bcl-2 and the translocation of Bax to mitochondria, but also increase the release of cytochrome c and the activation of caspase-3. In contrast, both GluR6 antisense ODNs (oligodeoxynucleotides) and 6,7,8,9-tetrahydro-5-nitro-1 H-benz[g]indole-2,3-dione-3-oxime (NS102), an antagonist of GluR6 receptor, prevented the above effects of preconditioning, which shows that suppressing the expression of GluR6 or inhibiting GluR6 activity contributes negatively to preconditioning-induced ischemia tolerance. Taken together, our results indicate that preconditioning can inhibit the over-assembly of the GluR6–PSD95–MLK3 signaling module and the JNK3 activation. GluR6 subunit-containing kainite receptors play an important role in the preconditioning-induced neuronal survival and provide new insight into stroke therapy.

Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus

JNK signaling pathway is activated and involved in the selective neuronal death in the hippocampal CA1 subfield following cerebral ischemia. However, little is known about upstream partner controlling the pathway. Here we reported that ischemia/reperfusion significantly elevated Cdc42 activity, enhanced assembly of the Cdc42-MLK3 complex and activation of JNK pathway. Most importantly, knock-down endogenous Cdc42 selectively suppressed the MLK3/MKK7/JNK3 cascade, and subsequently blocked the phosphorylation of c-Jun and FasL expression. Meanwhile, Bcl-2 was inactivated and the release of cytochrome c was diminished. These alterations eventually perturbed the caspase-3 activation as well as post-ischemic neuronal cell death. Taken together, our findings strongly suggest that Cdc42 serves as an upstream activator and modulates JNK-mediated apoptosis machinery in vivo, which ultimately results in neuronal apoptosis via nuclear and non-nuclear pathways. Thus, Cdc42 may be a potential therapeutic target in ischemic brain injury.

Neuroprotection of Tat-GluR6-9c against Neuronal Death Induced by Kainate in Rat Hippocampus via Nuclear and Non-nuclear Pathways

Previous studies have suggested that glutamate receptor 6 (GluR6) subunit- and JNK-deficient mice can resist kainate-induced epileptic seizure and neuronal toxicity (Yang, D. D., Kuan, C.-Y., Whitmarsh, A. J., Rinoćn, M., Zheng, T. S., Davis, R. J., Rakic, P., and Flavell, R. A. (1997) Nature 389, 865-870; Mulle, C., Seiler, A., Perez-Otano, I., Dickinson-Anson, H., Castillo, P. E., Bureau, I., Maron, C., Gage, F. H., Mann, J. R., Bettler, B., and Heinemmann, S. F. (1998) Nature 392, 601-605). In this study, we show that kainate can enhance the assembly of the GluR6-PSD95-MLK3 module and facilitate the phosphorylation of JNK in rat hippocampal CA1 and CA3/dentate gyrus (DG) subfields. More important, a peptide containing the Tat protein transduction sequence (Tat-GluR6-9c) perturbed the assembly of the GluR6-PSD95-MLK3 signaling module and suppressed the activation of MLK3, MKK7, and JNK. As a result, the inhibition of JNK activation by Tat-GluR6-9c diminished the phosphorylation of the transcription factor c-Jun and down-regulated Fas ligand expression in hippocampal CA1 and CA3/DG regions. The inhibition of JNK activation by Tat-Glur6-9c attenuated Bax translocation, the release of cytochrome c, and the activation of caspase-3 in CA1 and CA3/DG subfields. Furthermore, kainate-induced neuronal loss in hippocampal CA1 and CA3 subregions was prevented by intracerebroventricular injection of Tat-Glur6 - 9c. Taken together, our findings strongly suggest that the GluR6-PSD95-MLK3 signaling module mediates activation of the nuclear and non-nuclear pathways of JNK, which is involved in brain injury induced by kainate. Tat-GluR6-9c, the peptide we constructed, gives new insight into seizure therapy.

Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase (JNK) via nuclear and non-nuclear pathways

Our previous studies and the others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. Here we reported that Tat-JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), a smaller 11-mer peptide corresponding to residues 153–163 of murine JIP-1 conjugated to Tat peptide, perturbed the assembly of JIP-1–JNK3 complexes, thus inhibiting the activation of JNK3 induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. As a result, Tat-JBD diminished the increased phosphorylation of c-Jun (a nuclear substrate of JNK) and the increased expression of Fas ligand induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. At the same time, through inhibiting phosphorylation of Bcl-2 (a cytosolic target of JNK) and the release of Bax from Bcl-2/Bax dimers, Tat-JBD attenuated Bax translocation to mitochondria and the release of cytochrome c induced by ischemia/reperfusion. Furthermore, the activation of caspase3 and hydrolyzation of poly-ADP-ribose-polymerase induced by brain ischemia/reperfusion were also significantly suppressed by preinfusion of the peptide Tat-JBD. Importantly, Tat-JBD showed neuroprotective effects on ischemic brain damage in vivo, and administration of the peptide after ischemia also achieved the same effects as preinfusion of the peptide did. Thus, our findings imply that Tat-JBD induced neuroprotection against ischemia/reperfusion in rat hippocampal CA1 region via inhibiting nuclear and non-nuclear pathways of JNK signaling. Taken together, these results indicate that Tat-JBD peptide provides a promising therapeutic approach for ischemic brain injury.

Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence

It is well documented that N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors play a pivotal role in ischaemic brain injury. Recent studies have shown that kainate (KA) receptors are involved in neuronal cell death induced by seizure, which is mediated by the GluR6*PSD-95*MLK3 signalling module and subsequent c-Jun N-terminal kinase (JNK) activation. Here we investigate whether GluR6 mediated JNK activation is correlated with ischaemic brain injury. Our results show that cerebral ischaemia followed by reperfusion can enhance the assembly of the GluR6*PSD-95*MLK3 signalling module and JNK activation. As a result, activated JNK can not only phosphorylate the transcription factor c-Jun and up-regulate Fas L expression but can also phosphorylate 14-3-3 and promote Bax translocation to mitochondria, increase the release of cytochrome c and increase caspase-3 activation. These results indicate that GluR6 mediated JNK activation induced by ischaemia/reperfusion ultimately results in neuronal cell death via nuclear and non-nuclear pathways. Furthermore, the peptides we constructed, Tat-GluR6-9c, show a protective role against neuronal death induced by cerebral ischaemia/reperfusion through inhibiting the GluR6 mediated signal pathway. In summary, our results indicate that the KA receptor subunit GluR6 mediated JNK activation is involved in ischaemic brain injury and provides a new approach for stroke therapy.

Cytosolic Action of Thyroid Hormone Leads to Induction of Hypoxia-Inducible Factor-1α and Glycolytic Genes

Thyroid hormone (TH) effects are mediated through T(3), which regulates gene expression by binding to the nuclear TH receptors, TRalpha and TRbeta. Using microarrays and real-time PCR we found mRNAs of the following genes increased in response to T(3) in a TRbeta-specific manner: the transcription factor hypoxia-inducible factor (HIF)-1alpha, its target genes glucose transporter (GLUT)1 and platelet-type phosphofructokinase (PFKP), and the monocarboxylate transporter (MCT)4. The products of these genes have important roles in cellular glucose metabolism. HIF-1alpha expression and activity can be regulated through phosphatidylinositol-OH-3-kinase (PI3K) and MAPK signaling; thus the possibility of alternative, nonnuclear pathways of TH action was raised. We examined the involvement of these pathways in mediating TH effects by treating human skin fibroblasts with 2 nm T(3) in the absence or presence of either the PI3K inhibitor LY294002 or the MAPK inhibitor PD98059. T(3) induced HIF-1alpha mRNA by 2.7-fold (+/-0.4; P < 0.013). This increase was completely abrogated by LY294002 (1.1 +/- 0.1; nonsignificant = 0.57), but preserved in the presence of PD98059 (2.2 +/- 0.2; P < 0.009). Western blotting confirmed these results at the protein level, indicating dependency on the PI3K pathway. The same pattern of response was observed for GLUT1, PFKP, and MCT4 expression. To examine whether HIF-1alpha is directly induced, we used the translation inhibitor cycloheximide (CHX). T(3) induction of HIF-1alpha mRNA was not affected by CHX, whereas T(3) effect on GLUT1, PFKP, and MCT4 mRNA was completely abrogated by CHX. These results demonstrate that cytosolic activation of the PI3K signaling pathway has a role in TH-mediated direct (HIF-1alpha) and indirect (GLUT1, PFKP, MCT4) gene expression, and possibly provides a link between TH and cellular glucose metabolism in human fibroblasts.

The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in brain ischemia. To further study the roles of JNK activation in hippocampal CA1 neurons in a rat model of transient global ischemia, we assessed the effect of JNK inhibition by SP600125 on the degree of brain injury. Our results demonstrated that SP600125 significantly increased the number of surviving cells in hippocampal CA1 subfield and decreased the activation of p-JNK1/2 and p-JNK3 at 30 min and 3 days after brain ischemia. Moreover, SP600125 significantly diminished the increased levels of phosphorylated-c-Jun (Ser63/73) and phosphorylated-Bcl-2 (Ser87) at 3 h after brain ischemia. These results indicate that SP600125, a new inhibitor of JNK, protected transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region at least via suppressing the activation of nuclear substrate (c-Jun) and inactivating non-nuclear substrate (Bcl-2) induced by ischemic insult. Thus, inhibiting JNK activity by SP600125 may represent a new and effective strategy to treat ischemic stoke.

Efficient Nuclear Targeting of Granzyme B and the Nuclear Consequences of Apoptosis Induced by Granzyme B and Perforin Are Caspase-dependent, but Cell Death Is Caspase-independent

The secretory lysosomes of cytolytic lymphocytes house the principal apoptotic molecules for eliminating virus-infected cells: a membranolytic agent, perforin, and the serine protease, granzyme B. Perforin allows granzyme B access to cytosolic and nuclear substrates that, when cleaved, result in the characteristic apoptotic phenotype. Key among these substrates is a family of cytoplasmic caspases that mediate cell suicide. We have examined the caspase dependence of several nuclear and cytoplasmic parameters of apoptosis induced by purified perforin and granzyme B. Cell membrane leakage in response to perforin and granzyme B was independent of caspase activation; however, nuclear events such as DNA fragmentation and nuclear condensation and disintegration were abolished by the broad-acting caspase inhibitor, z-VAD-fmk. Despite being spared from nuclear damage, z-VAD-fmk-treated cells exposed to both cytotoxins uniformly died when they were re-cultured, while cells exposed to perforin or granzyme alone survived and proliferated as readily as untreated cells. Pretreatment of cells with z-VAD-fmk also resulted in reduced granzyme B nuclear uptake following addition of perforin; however, its uptake into the cytoplasm in the absence of perforin was unaffected. We conclude that cell death in response to perforin and granzyme B does not require caspase activation and still proceeds efficiently through non-nuclear pathways when nuclear substrate cleavage is inhibited.

Apparent nonnuclear regulation of intestinal phosphate transport: effects of 1,25-dihydroxyvitamin D3,24,25-dihydroxyvitamin D3, and 25-hydroxyvitamin D3.

The steroid hormone 1,25-(OH)2D3 modulates a number of cellular functions through nonnuclear pathways, particularly the stimulation of intestinal calcium transport (transcaltachia). The present studies determined whether 1,25-(OH)2D3 rapidly enhanced phosphate transport in the perfused duodenal loop of normal chicks. Vascular perfusion with 65 pM 1,25-(OH)2D3 significantly stimulated the appearance of 33P in the venous effluent within 2-8 min, reaching an average of 160% of control levels by 40 min. Lumenal perfusion with hormone failed to augment levels of 33P in the venous effluent. Vascular perfusion with a range of 1,25-(OH)2D3 concentrations yielded an apparent biphasic dose-response curve. Two additional vitamin D metabolites, 24,25(OH)2D3 and 25(OH)D3, which initiate transcaltachia, were tested for their effect on phosphate transport. Neither 6.5 nM 24,25(OH)2D3 nor 100 nM 25(OH)D3 stimulated 33P movement from the lumen to the venous effluent. When duodena were vascularly perfused with 65 pM 1,25-(OH)2D3 and either 6.5 nM 24,25(OH)2D3 or 100 nM 25(OH)D3, enhanced phosphate transport was attentuated or abolished. Phosphate transport was also analyzed at metabolite levels 5-fold lower or higher than those in normal chicks. For 24,25(OH)2D3, 1.3 nM metabolite did not augment phosphate transport, although stimulation did occur at 32.5 nM steroid (180 +/- 0.2% of controls). For 25(OH)D3, no stimulation was observed at 500 nM metabolite, whereas 20 nM steroid resulted in transport that was 160 +/- 0.14% of controls. The presence or absence of lumenal Ca2+ did not influence phosphate transport in duodena vascularly perfused with control medium, 65 pM 1,25-(OH)2D3, or 6.5 nM 24,25(OH)2D3. In contrast, vascular perfusion with 100 nM 25(OH)D3 stimulated phosphate transport when lumenal Ca2+ was present but not when it was absent. The influence of lumenal P(i) on transcaltachia was then studied. Although 65 pM 1,25-(OH)2D3, 6.5 nM 24,25(OH)2D3, and 100 nM 25(OH)D3, initiate transcaltachia in the presence of lumenal P(i), the absence of the anion abolished the stimulatory effects of 1,25-(OH)2D3 and 24,25(OH)2D3 on calcium transport but not those induced by 25(OH)D3. These data suggest a complex regulation of both calcium and phosphate transport based on relative levels of circulating vitamin D metabolites as well as the ionic content of the lumen.

Apparent nonnuclear regulation of intestinal phosphate transport: effects of 1,25-dihydroxyvitamin D3,24,25-dihydroxyvitamin D3, and 25- hydroxyvitamin D3

The steroid hormone 1,25-(OH)2D3 modulates a number of cellular functions through nonnuclear pathways, particularly the stimulation of intestinal calcium transport (transcaltachia). The present studies determined whether 1,25-(OH)2D3 rapidly enhanced phosphate transport in the perfused duodenal loop of normal chicks. Vascular perfusion with 65 pM 1,25-(OH)2D3 significantly stimulated the appearance of 33P in the venous effluent within 2-8 min, reaching an average of 160% of control levels by 40 min. Lumenal perfusion with hormone failed to augment levels of 33P in the venous effluent. Vascular perfusion with a range of 1,25-(OH)2D3 concentrations yielded an apparent biphasic dose-response curve. Two additional vitamin D metabolites, 24,25(OH)2D3 and 25(OH)D3, which initiate transcaltachia, were tested for their effect on phosphate transport. Neither 6.5 nM 24,25(OH)2D3 nor 100 nM 25(OH)D3 stimulated 33P movement from the lumen to the venous effluent. When duodena were vascularly perfused with 65 pM 1,25-(OH)2D3 and either 6.5 nM 24,25(OH)2D3 or 100 nM 25(OH)D3, enhanced phosphate transport was attentuated or abolished. Phosphate transport was also analyzed at metabolite levels 5-fold lower or higher than those in normal chicks. For 24,25(OH)2D3, 1.3 nM metabolite did not augment phosphate transport, although stimulation did occur at 32.5 nM steroid (180 +/- 0.2% of controls). For 25(OH)D3, no stimulation was observed at 500 nM metabolite, whereas 20 nM steroid resulted in transport that was 160 +/- 0.14% of controls. The presence or absence of lumenal Ca2+ did not influence phosphate transport in duodena vascularly perfused with control medium, 65 pM 1,25-(OH)2D3, or 6.5 nM 24,25(OH)2D3. In contrast, vascular perfusion with 100 nM 25(OH)D3 stimulated phosphate transport when lumenal Ca2+ was present but not when it was absent. The influence of lumenal P(i) on transcaltachia was then studied. Although 65 pM 1,25-(OH)2D3, 6.5 nM 24,25(OH)2D3, and 100 nM 25(OH)D3, initiate transcaltachia in the presence of lumenal P(i), the absence of the anion abolished the stimulatory effects of 1,25-(OH)2D3 and 24,25(OH)2D3 on calcium transport but not those induced by 25(OH)D3. These data suggest a complex regulation of both calcium and phosphate transport based on relative levels of circulating vitamin D metabolites as well as the ionic content of the lumen.

Thermogenesis and thyroid function.

The past 10 years have seen tremendous progress in the definition of the nuclear mechanism of action of thyroid hormones. Although the way in which these nuclear mechanisms underlie the 3,5,3'-triiodo-L-thyronine (T3)-dependent stimulation of metabolic rate remains to be clarified, evidence favoring non-nuclear pathways is limited. Clearly, T3 stimulates both the production and consumption of energy within cells. It also exerts a number of parallel effects that result in increased oxygen consumption, e.g. on mitochondrial structure and composition; on the metabolism of lipids, carbohydrates, and proteins, and on cardiac function. Additionally, T3 may increase the proton permeability of the inner mitochondrial membrane, which implies that it may decrease the efficiency of energy production. These metabolic effects of T3 appear to be restricted to homeothermic-animals, representing a coordinated response to the challenge of maintaining body temperature.

Glucocorticoid action: a mechanism involving nuclear and non-nuclear pathways.

Journal Article Glucocorticoid action: a mechanism involving nuclear and non‐nuclear pathways Get access L. K. JOHNSON, L. K. JOHNSON Department of Pathology, Stanford University School of Medicine, and the Geriatric Research, Education and Clinical Center, Palo Alto Veterans Administration Medical Center, Palo Alto, California 94304 *L. K. Johnson, GRECC‐182B, Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, California 94304, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar J. P. LONGENECKER, J. P. LONGENECKER Department of Pathology, Stanford University School of Medicine, and the Geriatric Research, Education and Clinical Center, Palo Alto Veterans Administration Medical Center, Palo Alto, California 94304 Search for other works by this author on: Oxford Academic Google Scholar J. D. BAXTER, J. D. BAXTER Metabolic Research Unit and Howard Hughes Medical Institute Laboratories, University of California, San Francisco, California 94143 Search for other works by this author on: Oxford Academic Google Scholar M. F. DALLMAN, M. F. DALLMAN Department of Physiology, University of California, San Francisco, California 94143, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar E. P. WIDMAIER, E. P. WIDMAIER Department of Physiology, University of California, San Francisco, California 94143, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar N. L. EBERHARDT N. L. EBERHARDT Metabolic Research Unit and Howard Hughes Medical Institute Laboratories, University of California, San Francisco, California 94143 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 107, Issue s23, 1 November 1982, Pages 6–23, https://doi.org/10.1111/j.1365-2133.1982.tb01026.x Published: 01 November 1982