Impaired production of nerve growth factor in the submandibular gland of diabetic mice

The production of nerve growth factor (NGF) in submandibular glands was examined in two kinds of diabetic mice. In genetically diabetic (C57BL/KsJ db/db) mice, which manifest marked insulin resistance and hyperglycemia, the concentration of NGF in the submandibular gland was less than one-tenth that of the nondiabetic controls. In streptozotocin-induced diabetic C57BL/KsJ mice, which show pancreatic insulitis leading to insulin deficiency and hyperglycemia, the glandular NGF concentration fell in a time-dependent manner to 26% of control level at 5 wk after the streptozotocin injection. A daily administration of insulin to the streptozotocin-induced diabetic mice restored the NGF concentration to almost the control level. The molecular size of NGF (13 kDa) in the glandular extracts of the genetically diabetic (db/db) mice in Western blots was indistinguishable from that of the control mice, but its level was reduced in the glands of the diabetic (db/db) animals. Although plasma NGF concentrations were normally below the sensitivity of the assay (less than 0.80 ng/ml) in both the control and the diabetic (db/db) mice, administration of cyclocytidine, which stimulates NGF release from the submandibular gland into the blood circulation, increased the plasma NGF level to 5.95 ng/ml in the control mice, but it failed to do so in the diabetic (db/db) mice. These findings suggest that, in diabetic mice, NGF production in the submandibular gland and its capacity to release NGF into the circulation are decreased.

Download Full-text

Role of Nerve Growth Factor in Cutaneous Wound Healing: Accelerating Effects in Normal and Healing-impaired Diabetic Mice

Journal of Experimental Medicine ◽

10.1084/jem.187.3.297 ◽

1998 ◽

Vol 187 (3) ◽

pp. 297-306 ◽

Cited By ~ 148

Author(s):

Hiroshi Matsuda ◽

Hiromi Koyama ◽

Hiroaki Sato ◽

Junko Sawada ◽

Atsuko Itakura ◽

...

Keyword(s):

Wound Healing ◽

Nerve Growth Factor ◽

Growth Factor ◽

Granulation Tissue ◽

Messenger Rna ◽

Biological Activities ◽

Serum Levels ◽

Blood Stream ◽

Diabetic Mice ◽

Nerve Growth

Four full-thickness skin wounds made in normal mice led to the significant increase in levels of nerve growth factor (NGF) in sera and in wounded skin tissues. Since sialoadenectomy before the wounds inhibited the rise in serum levels of NGF, the NGF may be released from the salivary gland into the blood stream after the wounds. In contrast, the fact that messenger RNA and protein of NGF were detected in newly formed epithelial cells at the edge of the wound and fibroblasts consistent with the granulation tissue produced in the wound space, suggests that NGF was also produced at the wounded skin site. Topical application of NGF into the wounds accelerated the rate of wound healing in normal mice and in healing-impaired diabetic KK/Ta mice. This clinical effect of NGF was evaluated by histological examination; the increases in the degree of reepithelialization, the thickness of the granulation tissue, and the density of extracellular matrix were observed. NGF also increased the breaking strength of healing linear wounds in normal and diabetic mice. These findings suggested that NGF immediately and constitutively released in response to cutaneous injury may contribute to wound healing through broader biological activities, and NGF improved the diabetic impaired response of wound healing.

Download Full-text

Density-dependent nerve growth factor regulation of Gs-alpha RNA in pheochromocytoma 12 cells.

Molecular and Cellular Biology ◽

10.1128/mcb.10.6.3277 ◽

1990 ◽

Vol 10 (6) ◽

pp. 3277-3279 ◽

Cited By ~ 4

Author(s):

G Tjaden ◽

A Aguanno ◽

R Kumar ◽

D Benincasa ◽

R M Gubits ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

G Protein ◽

Alpha Subunit ◽

Low Density ◽

Dependent Manner ◽

Nerve Growth ◽

Density Dependent ◽

Stimulatory G Protein ◽

Gs Alpha

Nerve growth factor (NGF) affects levels of the alpha subunit of the stimulatory G protein (Gs-alpha) in pheochromocytoma 12 cells in a bidirectional, density-dependent manner. Cells grown at high density responded to NGF treatment with increased levels of Gs-alpha mRNA and protein. Conversely, in cells grown in low-density cultures, levels of this mRNA were lowered by NGF treatment.

Download Full-text

Thyroxine Increases Submandibular Gland Nerve Growth Factor and Epidermal Growth Factor Concentrations Precociously in Neonatal Mice: Evidence for Thyroid Hormone-Mediated Growth Factor Synthesis

Pediatric Research ◽

10.1203/00006450-198604000-00001 ◽

1986 ◽

Vol 20 (4) ◽

pp. 281-284 ◽

Cited By ~ 8

Author(s):

Peter Walker

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Thyroid Hormone ◽

Epidermal Growth Factor ◽

Submandibular Gland ◽

Nerve Growth ◽

Neonatal Mice ◽

Epidermal Growth

Download Full-text

Nerve Growth Factor Stimulates Multisite Tyrosine Phosphorylation and Activation of the Atypical Protein Kinase C's via a src Kinase Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.21.24.8414-8427.2001 ◽

2001 ◽

Vol 21 (24) ◽

pp. 8414-8427 ◽

Cited By ~ 66

Author(s):

Marie W. Wooten ◽

Michel L. Vandenplas ◽

M. Lamar Seibenhener ◽

Thangiah Geetha ◽

Maria T. Diaz-Meco

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Protein Kinase ◽

Tyrosine Phosphorylation ◽

Pc12 Cells ◽

Catalytic Domain ◽

Src Kinase ◽

Dependent Manner ◽

Nerve Growth ◽

Atypical Protein Kinase

ABSTRACT Atypical protein kinase C (PKC) isoforms are required for nerve growth factor (NGF)-initiated differentiation of PC12 cells. In the present study, we report that PKC-ι becomes tyrosine phosphorylated in the membrane coincident with activation posttreatment with nerve growth factor. Tyrosine phosphorylation and activation of PKC-ι were inhibited in a dose-dependent manner by both PP2 and K252a, src and TrkA kinase inhibitors. Purified src was observed to phosphorylate and activate PKC-ι in vitro. In PC12 cells deficient in src kinase activity, both NGF-induced tyrosine phosphorylation and activation of PKC-ι were also diminished. Furthermore, we demonstrate activation of src by NGF along with formation of a signal complex including the TrkA receptor, src, and PKC-ι. Recruitment of PKC-ι into the complex was dependent on the tyrosine phosphorylation state of PKC-ι. The association of src and PKC-ι was constitutive but was enhanced by NGF treatment, with the src homology 3 domain interacting with a PXXP sequence within the regulatory domain of PKC-ι (amino acids 98 to 114). Altogether, these findings support a role for src in regulation of PKC-ι. Tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. Y256F and Y271F mutations did not alter src-induced activation of PKC-ι, whereas the Y325F mutation significantly reduced src-induced activation of PKC-ι. The functional relevance of these mutations was tested by determining the ability of each mutant to support TRAF6 activation of NF-κB, with significant impairment by the Y325F PKC-ι mutant. Moreover, when the Y352F mutant was expressed in PC12 cells, NGF's ability to promote survival in serum-free media was reduced. In summary, we have identified a novel mechanism for NGF-induced activation of atypical PKC involving tyrosine phosphorylation by c-Src.

Download Full-text

Nerve growth factor synthesis by mouse submandibular gland cells in culture

Brain Research ◽

10.1016/0006-8993(93)90980-2 ◽

1993 ◽

Vol 628 (1-2) ◽

pp. 356

Author(s):

Margaret Fahnestock ◽

Qin Lu

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Submandibular Gland ◽

Nerve Growth ◽

Gland Cells ◽

Cells In Culture ◽

Nerve Growth Factor Synthesis

Download Full-text

Binding characteristics and apparent molecular size of detergent solubilized nerve growth factor receptor of sympathetic ganglia.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.76.7.3242 ◽

1979 ◽

Vol 76 (7) ◽

pp. 3242-3245 ◽

Cited By ~ 31

Author(s):

N. V. Costrini ◽

R. A. Bradshaw

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Growth Factor Receptor ◽

Molecular Size ◽

Sympathetic Ganglia ◽

Nerve Growth Factor Receptor ◽

Nerve Growth ◽

Binding Characteristics

Download Full-text

Spatial Distribution of Nociceptive Neuropeptide and Nerve Growth Factor Depletion in Experimental Diabetic Peripheral Nervous System

Journal of International Medical Research ◽

10.1177/147323000203000507 ◽

2002 ◽

Vol 30 (5) ◽

pp. 512-519 ◽

Cited By ~ 6

Author(s):

H Kanbayashi ◽

H Itoh ◽

T Kashiwaya ◽

K Atoh ◽

I Makino

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Substance P ◽

Dorsal Root ◽

Time Course ◽

Diabetic Control ◽

Diabetic Rats ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Nerve Growth

This study investigated the time-course of the nociceptive neuropeptide substance P and nerve growth factor (NGF), which facilitates substance P production, in lumbar and cervical dorsal root ganglia (DRG) of streptozotocin-induced diabetic rats. Levels of substance P and NGF were measured by radioimmunoassay and sandwich enzyme-linked immunosorbent assay, respectively, 2 months, 4 months and 8 months after induction of diabetes, and compared with age-matched non-diabetic control rats. At 2 months and 4 months, substance P and NGF levels were lower in the lumbar DRG of the diabetic rats than in controls. At 8 months, substance P and NGF were lower in both the lumbar and cervical DRG of the diabetic rats than in controls. These data demonstrate that a decrease in substance P levels in primary sensory neurons with NGF depletion occurs in an axonal length-dependent manner in diabetic rats, and that this decrease may be correlated with the duration of diabetes.

Download Full-text