| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Department of Cell Biology and Neuroanatomy, University of Minnesota Medical School, Minneapolis, Minnesota 55455
Address all correspondence and requests for reprints to: Robert L. Sorenson, Ph.D., Department of Cell Biology and Neuroanatomy, University of Minnesota Medical School, 4–157 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455. E-mail: soren{at}lenti.med.umn.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PRL treatment of INS-1 cells resulted in a 2- to 4-fold increase in cell proliferation compared to that in the control group. In contrast, there was no effect of PRL treatment on HIT cell proliferation and only a very small effect on RIN cell proliferation. A significant effect on INS-1 cell proliferation was observed at 10 ng/ml and reached a maximum at 200 ng/ml.
PRL treatment resulted in enhanced insulin secretion from INS-1 cells. There was a time-dependent increase in insulin secretion, which when corrected for cell number was 1.5-fold greater in the PRL-treated cells. The effects of PRL on cell division and insulin secretion were glucose dependent.
The presence of the JAK family of tyrosine kinases and the transcription factor STAT5 in INS-1 cells was examined by immunocytochemical techniques. Although all members of the JAK family of kinases were detected, the staining intensity of JAK-2 was noticeably more intense. Initial studies of STAT5 translocation were performed using PRL-dependent Nb2 lymphoma cells, in which PRL treatment resulted in a nearly complete translocation of cytoplasmic STAT5 to the nucleus. Under control conditions there was a near-equal fluorescence intensity of STAT5 staining in the nucleus and cytoplasm of INS-1 cells. PRL treatment resulted in a time-dependent increase in STAT5 staining in the nucleus, with a corresponding decrease in the cytoplasm. The STAT5 staining intensity in the nucleus remained elevated for the duration of PRL treatment. This effect was reversible upon removal of PRL from the medium. Besides PRL, both GH and FBS induced a similar translocation of STAT5 to the nucleus. Although present in RIN cells, no detectable changes in STAT5 were observed in RIN cells after exposure to PRL, GH, or FBS.
INS-1 cells should provide a good model for further inquiry into the intracellular signaling pathways used by PRL and how these events alter islet function.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Similarly, in vitro and in vivo experiments examining the effects of the homologous PRL or placental lactogen on islets indicate that hormones of lactogenic specificity induce the same changes in islets observed during pregnancy. These changes include 1) enhancement of glucose-stimulated insulin secretion and a decreased glucose stimulation threshold (14, 15), 2) increased ß-cell proliferation and islet volume (15, 16, 17, 18, 19), 3) increased insulin synthesis (20), 4) increased gap junctional coupling among ß-cells (14, 15), 5) increased PRL receptor messenger RNA (11), and 6) increased glucose utilization and oxidation (13, 16). Based on these observations, we have proposed that placental lactogen is the key regulatory hormone for adaptation of islets to pregnancy in rat islets, and placental lactogen and/or PRL are the principal hormones involved during human pregnancy (17, 18).
Although these studies have demonstrated the regulation of islet function by lactogens, the absence of a lactogen-responsive ß-cell line has limited studies into the intracellular signaling pathways used by PRL receptors. Although RIN cells have PRL receptors (19, 20), human GH, which binds to both rat (r) GH and PRL receptors, has a relatively small effect on cell division, insulin secretion, and insulin content in these cells (21). Recently, INS-1 cells have been introduced as a model ß-cell line (22). These cells are well granulated and release insulin in response to glucose. Importantly, these cells appeared to be responsive to PRL (23, 24). In this report, we further characterized the effect of PRL on INS-1 cells, with particular emphasis on PRL-induced translocation of STAT5 from the cytoplasm to the nucleus.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Growth studies
Cells were plated in growth medium at 10–15% confluence in
24-well cluster plates (Costar, Cambridge, MA). After 24 h, the
cells were washed twice with basal medium and cultured in this medium
for the duration of the experiment. Hormones or vehicle control were
added to each well, and the medium was changed daily. For growth
curves, cells from replicate plates were trypsinized and counted in
quadruplicate each day using a ZBI Coulter particle counter (Coulter
Electronics, Hialeah, FL). For dose-response and growth comparison
experiments, cell counts from day 5 or 6 (representing log phase
growth) were used. rPRL and rGH were obtained from the National Hormone
and Pituitary Program, NIH (Baltimore, MD).
Insulin secretion
Daily insulin secretion was monitored in the culture medium
during cell growth experiments. Medium was collected from each well
every 24 h and stored at -20 C, and mean insulin secretion was
determined by RIA (28) using rat insulin standards (Linko, St. Louis,
MO).
Immunocytochemistry
Attached cells were plated in growth medium on
22-mm2 glass coverslips at 10–15% confluence and changed
to basal medium after 2 days. Nb2 cells were grown in T-25 culture
flasks (Costar, Cambridge, MA) and maintained at a concentration below
106 cells/ml. After hormone treatment for the specified
times, the cells were washed in PBS, fixed in 4% paraformaldehyde for
20 min at room temperature, and then again thoroughly rinsed in PBS.
The primary antibodies were diluted in PBS containing 0.3% Triton
X-100, 1% normal donkey serum, 1% BSA, and 0.02% sodium azide. The
cells were incubated in the primary antibodies overnight at 4 C. After
rinsing (six times) in PBS containing 0.1% Triton X-100, the cells
were incubated in the secondary antibodies for 4 h at room
temperature.
Primary antibodies, rabbit anti-STAT5 (1:200), rabbit anti-JAK1 (1:200), goat anti-JAK3 (1:200), and rabbit anti-Tyk2 (1:200) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). The STAT5 antibody recognizes both STAT5a and STAT5b. Rabbit anti-JAK2 (1:200) was obtained from Upstate Biotechnology (Lake Placid, NY). The following secondary antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA) were used in these studies: FITC-labeled donkey antirabbit IgG (1:150), cyanine 3.18-labeled donkey antirabbit IgG (1:400), and cyanine 3.18-labeled donkey antigoat IgG (1:400). In the absence of the primary antisera, there was no detectable staining.
The immunostained specimens were examined using a Bio-Rad MRC-1000 confocal microscope equipped with a krypton/argon laser (Bio-Rad Life Science Group, Hercules, CA). Final image processing was performed using the Confocal Assistant program written by T. C. Brelje (Department of Cell Biology and Neuroanatomy, University of Minnesota) and Adobe Photoshop; printing was performed using a Fuji Pictrograph 3000 digital printer (Tokyo, Japan). Details of these procedures have been previously reported (29, 30).
Assessment of STAT5 translocation to the nucleus was conducted using Metamorph 2.0 image analysis software (Universal Imaging Corp., West Chester, PA). The average pixel intensity was measured in the cytoplasm and nucleus of individual cells, and the ratio was calculated for 100 cells in each treatment group.
Statistical analysis
All experiments were repeated 3–5 times, with comparable
results obtained in the replicates. Within each experiment there were
between 4–8 samples/group. For quantitative immunohistochemistry, 100
cells were examined for each group. The results are presented as those
typical for each experiment, and the data are expressed as the
mean ± SEM. Statistical analysis was performed using
Student’s t test or ANOVA with post-hoc tests
for determining significance among groups.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
).
|
, left
panel).
|
, right
panel).
To examine the effect of PRL on insulin secretion from INS-1 cells,
culture media were changed daily, and the cumulative insulin secreted
into the media was determined. Insulin secretion from the PRL-treated
cells was significantly increased by day 2 of the experiment
(P < 0.001). After 6 days of culture, there was a
2.5-fold greater amount of insulin secreted by the PRL-treated cells
(Fig. 3, left panel). As PRL treatment
results in an increased number of cells, the amount of insulin secreted
was normalized by the number of cells on each day of the experiment.
These data are reported as microunits of insulin secreted per 24 h/1000
cells (Fig. 3, right panel). Insulin secretion in the
control cells was about 7 µU per 24 h/1000 cells for the first 2 days
of the experiment and was reduced to approximately 2 µU per 24 h/1000
cells for days 3–6 of culture. PRL-treated cells had an insulin
secretion rate similar to the control cells for the first 2 days of
culture. Although there was a reduction of insulin secretion in the
PRL-treated cells on days 3–6 of culture, the insulin secretion rate
was about 1.5-fold greater in the PRL-treated cells than in the control
cells (P < 0.005).
|
, left
panel) and cumulative insulin secretion (Fig. 4, right
panel) on day 6 of the experiment. Although PRL stimulated cell
proliferation at both 4.2 and 10.0 mM glucose, there was a
significant enhancement of PRL’s effect at the higher level of
glucose. In the insulin secretion studies, PRL significantly increased
insulin secretion under both low and high glucose conditions. However,
there was no indication of glucose potentiation of PRL-stimulated
insulin secretion.
|
). To determine whether other
members of the JAK family had a similar staining pattern, JAK-1, JAK-3,
and Tyk-2 were also examined. All three were observed in INS-1 cells
and showed a staining intensity in the nucleus as well as the cytoplasm
(Fig. 5).
|
Effect of PRL on STAT5 translocation in Nb2 cells and INS-1
cells
As cell proliferation in Nb2 cells is dependent on PRL, initial
studies included Nb2 cells and INS-1 cells. The cells were cultured in
basal medium 24 h before treatment with 200 ng/ml rPRL for INS-1
cells and with 50 ng/ml rPRL for Nb2 cells. The cells were then
examined by immunocytochemistry for STAT5 at time zero and 1 h
after the addition of PRL. In both Nb2 cells and INS-1 cells STAT5 was
detected in the nucleus as well as the cytoplasm. After PRL treatment
for 1 h, there was a large increase in STAT5 immunofluorescence in
the nucleus in Nb2 cells and INS-1 cells (Fig. 6). The
staining pattern in individual cells appeared to be particulate or
vesicular, with a range of staining intensities in both the nucleus and
cytoplasm (Figs. 6 and 8, A and B). The vast majority of cells were of
this appearance; however, there were a few cells (<0.1%) in which
there was a very high level of staining intensity (Figs. 6C and 8C).
|
|
, A–C). Immunofluorescence was determined
in the nucleus and cytoplasm of 100 cells for each treatment group, and
the nuclear/cytoplasmic fluorescence ratio was calculated (Fig. 10, left panel). The ratio was 1.42 ±
0.02 (range, 1.00–2.22) at time zero and increased to 1.64 ±
0.03 (range, 1.2 to 3.2) in the 5 min group (P <
0.001). This ratio further increased to 2.66 ± 0.05 (range,
1.66–3.34) in the 30 min group and 2.84 ± 0.06 (range,
1.56–4.41) in the 60 min group. The range of ratios is provided to
show heterogeneity among the cells and also demonstrates that all cells
appear to respond to the PRL treatment. In some experiments, earlier
time points were examined, and STAT5 translocation was observed as
early as 2 min after PRL treatment. At this early time point, STAT5
appeared to coalesce at the margin of the nucleus in some cells,
whereas in others there was already an indication of STAT5 transfer
into the nucleus (Fig. 9).
|
|
|
, D–F). The
nuclear/cytoplasmic STAT5 ratio for time zero was 2.84 ± 0.04 and
decreased to 1.96 ± 0.03 by 0.5 h (P <
0.001). The ratio at 1 h was 1.52 ± 0.01, similar to the
values of 1.40 ± 0.02 and 1.41 ± 0.01 in the 2 and 24
h groups (Fig. 10, right panel).
Effects of FBS, rGH, and rPRL on STAT5 translocation in INS-1
cells
As FBS promotes INS-1 cell proliferation similar to that observed
with rPRL (Fig. 11) it was of interest to determine
whether it would also stimulate STAT5 translocation. For purposes of
comparison, rGH- and rPRL-treated groups were included in this STAT5
translocation experiment. INS-1 cells were cultured in basal medium for
24 h before the onset of the experiment. Then the medium was
changed to include 10% FBS, 200 ng/ml rGH, or 200 ng/ml rPRL. STAT5
immunohistochemistry was performed on the cells at 0 min, 5 min, and
1 h. For all treatment groups there was a detectable increase in
STAT5 immunofluorescence in the nucleus after 5 min of treatment. After
1 h of treatment, the STAT5 fluorescence intensity in the nucleus
was similar among the treatment groups (Fig. 12). The
mean nuclear/cytoplasmic STAT5 ratio ± SEM for time
zero was 1.50 ± 0.03. For the FBS treatment group, the ratio
increased to 2.04 ± 0.05 (P < 0.001) at 5 min
and 2.96 ± 0.07 at 1 h. For the rGH treatment group, the
ratio increased to 1.80 ± 0.05 (P < 0.001) at 5
min and 3.08 ± 0.08 at 1 h. For the rPRL treatment group,
the ratio increased to 1.69 ± 0.04 (P < 0.001)
at 5 min and 2.91 ± 0.08 at 1 h (Fig. 13).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Characteristics of PRL regulation of ß-cell division and insulin
secretion in INS-1 cells
Initial experiments were performed comparing the effects of rPRL
on HIT, RIN and INS-1 cell proliferation. These results showed that
INS-1 cells were particularly responsive to PRL treatment and were
chosen for further study. During the course of the experiments, PRL
treatment for 6 days resulted in a 2.2- to 4.3-fold increase in cell
number compared to the control value. These results were based on cell
count and are somewhat greater than previously observed in similar
experiments that were reported as DNA content per well and
[3H]thymidine incorporation (22, 23).
The effect of PRL on insulin secretion from isolated islets is well characterized (14, 15, 16, 17, 18, 20). It requires PRL treatment for more than 24 h to have a discernible effect and for up to 5 days to have a maximum effect. In cultured neonatal rat islets, PRL treatment results in about a 3-fold increase in insulin secretion, whereas in adult islets there is about a 1.5-fold increase in insulin secretion. Insulin secretion was examined in INS-1 cells throughout 6 days of culture with PRL. The cumulative insulin secretion was 2.5-fold greater in rPRL-treated cells. Since the cells were growing during the experiment, the data were also analyzed on the basis of cell number for insulin secreted per 24 h/1000 cells. A characteristic finding was that insulin secretion decreases after 2 days of culture for both control and PRL-treated cells. Subsequently, insulin secretion from the PRL-treated cells was increased about 1.5-fold compared to that from the controls. Interestingly, this increase compares favorably with that observed in adult islets in culture (18). However, it should be pointed out that insulin secretion from INS-1 cells is considerably less than that observed in isolated islets. For example, cultured adult islets secrete about 100–200 µU insulin per 24 h/1000 cells, whereas INS-1 cells secrete less than 10 µU insulin per 24 h/1000 cells. The lower insulin secretion by INS-1 cells appears to be commensurate with their lower insulin content relative to that of ß-cells (22).
Another feature of PRL-treated islets is that the effect of PRL on cell division and insulin secretion is glucose dependent (31). Similar to cultured islets, PRL-stimulated INS-1 cell proliferation was observed at both 4.2 and 10.0 mM glucose. However, the increase in insulin secretion at low glucose in PRL-stimulated INS-1 cells is different from that observed in cultured islets. This difference may be the result of the abnormally lower threshold for glucose-stimulated insulin secretion observed in INS-1 cells (22).
These experiments indicate that PRL treatment of INS-1 cells results in enhanced cell proliferation and insulin secretion similar to those observed in PRL-treated islets and islets during pregnancy. Thus, as presently characterized, INS-1 cells should provide a good model for examining details of PRL/placental lactogen regulation of ß-cell division and insulin secretion.
Characteristics of the PRL signaling pathway in INS-1 cells
In a previous immunocytochemical study, we examined the cellular
location of JAK-2 in Nb2 cells, islets, and several other tissues (10).
In these cells JAK-2 was present in the cytoplasm in what appeared to
be vesicular structures and was very prominent in the nucleus, but
absent from the nucleolus. In the present study, a similar pattern of
JAK-2 was observed in INS-1 cells. When JAK-1, JAK-3, and Tyk-2
cellular staining was examined in INS-1 cells, a comparable
distribution of immunofluorescence was observed. These experiments show
that all members of the JAK family are expressed in INS-1 cells, but
also demonstrate that these enzymes are prominent features of the
nucleus. The regulation and role of these kinases in the nucleus are
unclear. While this manuscript was in preparation, Lobie et
al. reported additional evidence for the presence of JAK kinases
in the nucleus (43).
Initial studies of STAT5 translocation were performed using Nb2 lymphoma cells. The Nb2 cells were examined because growth of these cells is dependent on PRL and is a well established model cell line for the study of PRL regulation (44). In control Nb2 cells, there was a uniform presence of STAT5 in the cytoplasm and nucleus, but not the nucleolus. In these cells, PRL treatment resulted in a nearly complete translocation of cytoplasmic STAT5 to the nucleus.
In INS-1 cells, under control conditions, there was a near-uniform distribution of STAT5 in the cytoplasm and nucleus. The staining pattern of STAT5 suggests that it may be segregated in particles or vesicles with varying staining intensities. This is especially suggestive in the rare cells in which there is a very high degree of staining and in the early stages of STAT5 translocation when STAT5 particles appear to coalesce at the nuclear margin. Whether the apparent particulate nature of STAT5 is real and of significance or is an artifact of fixation cannot be determined from the present experiments. The presence of STAT5 in the nucleus of untreated FS2 fibroblasts has been previously demonstrated. In that report the resident nuclear STAT5 appeared to be unphosphorylated, and it was only the cytoplasmic STAT5, once phosphorylated, that was translocated to the nucleus (36). It is likely that this is the case in INS-1 cells as well, but confirmation of this awaits further experimentation. At present, the function of the resident nuclear STAT5 is unknown.
PRL treatment resulted in a time-dependent translocation of STAT5 to
the nucleus. In the earliest stages, STAT5 appears to coalescence at
the nuclear margin. Translocation to the nucleus was observed within 5
min and was maximal by 30 min. The translocated STAT5 remained in the
nucleus as long as PRL was present. The maximum translocation in INS-1
cells was less than that observed in Nb2 cells, where an almost
complete translocation of STAT5 to the nucleus occurred. The nearly
complete translocation of STAT5 to the nucleus was reported for
interferon-
-treated fibroblasts (36). In contrast to the
interferon--treated fibroblasts, in which STAT5 started to leave the
nucleus by 30 min of treatment, STAT5 remained in the nucleus in INS-1
cells as long as PRL was present. After removal of PRL from the medium,
the nuclear localization of STAT5 was substantially reduced by 30 min
and was indistinguishable from controls after 1 h.
As FBS and GH are also growth factors for INS-1 cells (24), we examined their effects on STAT5 translocation. That study also showed that GH had a much greater effect on phosphorylation of JAK-2 than PRL, and FBS had no effect on JAK-2 phosphorylation. In this study, both GH and FBS treatment resulted in STAT5 translocation in a manner similar to that observed with PRL. It is of some interest that the report on JAK-2 phosphorylation of INS-1 cells indicated no effect of FBS (24), whereas the present study showed an effect of FBS on STAT5 translocation. This suggests that FBS-induced STAT5 translocation is mediated by a different member of the JAK family. In contrast to the effects of FBS, GH, and PRL on INS-1 cells, these treatments did not have an effect on STAT5 translocation in RIN cells. This correlates with the very small effect of PRL on growth of these cells.
In summary, we examined two of the principal characteristics, ß-cell growth and insulin secretion, of PRL-treated islets and islets from pregnancy in INS-1 cells. The response of INS-1 cells to PRL was similar to that of lactogen-treated islets, in that there was enhanced ß-cell proliferation and insulin secretion. Studies on the JAK-STAT pathway indicated the presence of all members of the JAK family in INS-1 cells. Analysis of STAT5 translocation was performed using quantitative immunocytochemical techniques. Under quiescent conditions there was a nearly equal fluorescence intensity of STAT5 in the nucleus and cytoplasm. PRL treatment resulted in translocation of STAT5 to the nucleus in a time-dependent manner, where it remained for the duration of PRL treatment. Removal of PRL from the medium resulted in a reversal of the translocation process. INS-1 cells should provide a good model for further inquiry into the intracellular signaling pathways used by rat lactogenic hormones and how the pathway segregates to regulate insulin secretion and cell division.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Supported by grants from the Swedish Medical Society and an Olga
Jonsson grant from Uppsala University Medical Faculty.
Received November 1, 1996.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
: tyrosine phosphorylation of a
92-kd DNA binding protein. Science 258:1808–1812. Science 261:1744–1746This article has been cited by other articles:
 |
|
 |
|
  M. M. Sachdeva and D. A. Stoffers Minireview: Meeting the Demand for Insulin: Molecular Mechanisms of Adaptive Postnatal ss-Cell Mass Expansion Mol. Endocrinol., June 1, 2009; 23(6): 747 - 758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Sorenson and T. C. Brelje Prolactin Receptors Are Critical to the Adaptation of Islets to Pregnancy Endocrinology, April 1, 2009; 150(4): 1566 - 1569. [Full Text] [PDF]
|
|
|
|
 |
|
 A. J Weinhaus, L. E Stout, N. V Bhagroo, T C. Brelje, and R. L Sorenson Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy J. Endocrinol., June 1, 2007; 193(3): 367 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cozar-Castellano, M. Haught, and A. F. Stewart The Cell Cycle Inhibitory Protein p21cip Is Not Essential for Maintaining {beta}-Cell Cycle Arrest or {beta}-Cell Function In Vivo Diabetes, December 1, 2006; 55(12): 3271 - 3278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cozar-Castellano, N. Fiaschi-Taesch, T. A. Bigatel, K. K. Takane, A. Garcia-Ocana, R. Vasavada, and A. F. Stewart Molecular Control of Cell Cycle Progression in the Pancreatic {beta}-Cell Endocr. Rev., June 1, 2006; 27(4): 356 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Johansson, G. Mattsson, A. Andersson, L. Jansson, and P.-O. Carlsson Islet Endothelial Cells and Pancreatic {beta}-Cell Proliferation: Studies in Vitro and during Pregnancy in Adult Rats Endocrinology, May 1, 2006; 147(5): 2315 - 2324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Cozar-Castellano, M. Weinstock, M. Haught, S. Velazquez-Garcia, D. Sipula, and A. F. Stewart Evaluation of {beta}-Cell Replication in Mice Transgenic for Hepatocyte Growth Factor and Placental Lactogen: Comprehensive Characterization of the G1/S Regulatory Proteins Reveals Unique Involvement of p21cip Diabetes, January 1, 2006; 55(1): 70 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Jensen, E. D Galsgaard, A. E Karlsen, Y. C Lee, and J. H Nielsen STAT5 activation by human GH protects insulin-producing cells against interleukin-1{beta}, interferon-{gamma} and tumour necrosis factor-{alpha}-induced apoptosis independent of nitric oxide production J. Endocrinol., October 1, 2005; 187(1): 25 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fujinaka, D. Sipula, A. Garcia-Ocana, and R. C. Vasavada Characterization of Mice Doubly Transgenic for Parathyroid Hormone-Related Protein and Murine Placental Lactogen: A Novel Role for Placental Lactogen in Pancreatic {beta}-Cell Survival Diabetes, December 1, 2004; 53(12): 3120 - 3130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Brelje, L. E. Stout, N. V. Bhagroo, and R. L. Sorenson Distinctive Roles for Prolactin and Growth Hormone in the Activation of Signal Transducer and Activator of Transcription 5 in Pancreatic Islets of Langerhans Endocrinology, September 1, 2004; 145(9): 4162 - 4175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Graichen, J. Sandstedt, E. L. K. Goh, O. G. P. Isaksson, J. Tornell, and P. E. Lobie The Growth Hormone-binding Protein Is a Location-dependent Cytokine Receptor Transcriptional Enhancer J. Biol. Chem., February 14, 2003; 278(8): 6346 - 6354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Lingohr, L. M. Dickson, J. F. McCuaig, S. R. Hugl, D. R. Twardzik, and C. J. Rhodes Activation of IRS-2--Mediated Signal Transduction by IGF-1, but not TGF-{alpha} or EGF, Augments Pancreatic {beta}-Cell Proliferation Diabetes, April 1, 2002; 51(4): 966 - 976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Brelje, A. M. Svensson, L. E. Stout, N. V. Bhagroo, and R. L. Sorenson An Immunohistochemical Approach to Monitor the Prolactin-induced Activation of the JAK2/STAT5 Pathway in Pancreatic Islets of Langerhans J. Histochem. Cytochem., March 1, 2002; 50(3): 365 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Holness and M. C. Sugden Dexamethasone during Late Gestation Exacerbates Peripheral Insulin Resistance and Selectively Targets Glucose-Sensitive Functions in {beta} Cell and Liver Endocrinology, September 1, 2001; 142(9): 3742 - 3748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Fleenor and M. Freemark Prolactin Induction of Insulin Gene Transcription: Roles of Glucose and Signal Transducer and Activator of Transcription 5 Endocrinology, July 1, 2001; 142(7): 2805 - 2810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Friedrichsen, E. D. Galsgaard, J. H. Nielsen, and A. Møldrup Growth Hormone- and Prolactin-Induced Proliferation of Insulinoma Cells, INS-1, Depends on Activation of STAT5 (Signal Transducer and Activator of Transcription 5) Mol. Endocrinol., January 1, 2001; 15(1): 136 - 148. [Abstract] [Full Text]
|
|
|
|
|
|
R. C. Vasavada, A. Garcia-Ocana, W. S. Zawalich, R. L. Sorenson, P. Dann, M. Syed, L. Ogren, F. Talamantes, and A. F. Stewart Targeted Expression of Placental Lactogen in the Beta Cells of Transgenic Mice Results in Beta Cell Proliferation, Islet Mass Augmentation, and Hypoglycemia J. Biol. Chem., May 12, 2000; 275(20): 15399 - 15406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Heitmeier, A. L. Scarim, and J. A. Corbett Prolonged STAT1 Activation Is Associated with Interferon-gamma Priming for Interleukin-1-induced Inducible Nitric-oxide Synthase Expression by Islets of Langerhans J. Biol. Chem., October 8, 1999; 274(41): 29266 - 29273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Galsgaard, J. H. Nielsen, and A. Moldrup Regulation of Prolactin Receptor (PRLR) Gene Expression in Insulin-producing Cells. PROLACTIN AND GROWTH HORMONE ACTIVATE ONE OF THE RAT PRLR GENE PROMOTERS VIA STAT5a AND STAT5b J. Biol. Chem., June 25, 1999; 274(26): 18686 - 18692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Herrington, L. Rui, G. Luo, L.-y. Yu-Lee, and C. Carter-Su A Functional DNA Binding Domain Is Required for Growth Hormone-induced Nuclear Accumulation of Stat5B J. Biol. Chem., February 19, 1999; 274(8): 5138 - 5145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-A. Huotari, J. Palgi, and T. Otonkoski Growth Factor-Mediated Proliferation and Differentiation of Insulin-Producing INS-1 and RINm5F Cells: Identification of Betacellulin as a Novel {beta}-Cell Mitogen Endocrinology, April 1, 1998; 139(4): 1494 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sjoholm, Q. Zhang, N. Welsh, A. Hansson, O. Larsson, M. Tally, and P.-O. Berggren Rapid Ca2+ Influx and Diacylglycerol Synthesis in Growth Hormone-mediated Islet beta -Cell Mitogenesis J. Biol. Chem., July 7, 2000; 275(28): 21033 - 21040. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
