Endocrinology Vol. 142, No. 11 4595-4598
Copyright © 2001 by The Endocrine Society
Editorial: Pulsatile Hormone Patterns Governing Transcription Factor Function
Jessica Schwartz
University of Michigan Medical School
Department of Physiology
Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Jessica Schwartz, Ph.D., University of Michigan Medical School, Department of Physiology, 6815 Medical Science II, Ann Arbor, Michigan 48109.
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Physiology of Episodic GH Secretion
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Since it was established that pituitary GH is
secreted in a pulsatile pattern (1, 2), the physiological
importance of the GH secretion pattern has been sought. Mechanisms by
which pulsatile GH secretion is determined by hypothalamic factors has
been extensively studied (3, 4, 5, 6), but the direct
physiological consequences of GH secretion patterns are less clear.
Critical insight into such physiology stemmed from observations that
the pattern of GH secretion was different in male and female rats
(7), in males characterized by abrupt peaks and deep
troughs with a periodicity of 3–4 h between peaks (pulsatile
secretion), and in females, less pronounced peaks and troughs (often
referred to as continuous secretion). Elucidation of these differences
in GH secretion patterns led to appreciation that they correspond with
sexual dimorphism in some responses to GH, particularly body growth
(8) and activities of male-specific and female-specific
enzymes of hepatic steroid metabolism (9). Sexual
dimorphism of other liver proteins dependent on pulsatile
vs. continuous GH include the induction of major urinary
proteins by pulsatile GH in male mice, and of liver PRL/GH receptors by
continuous GH in female mice (10). Experimental models
mimicking the male and female GH secretion patterns in vivo
and in vitro have established that a subset of genes
encoding liver cytochrome P450 (CYP) enzymes of steroid metabolism in
the CYP2 and CYP3 families are useful models for analysis of sexually
dimorphic genes whose expression is determined by the differences in GH
secretion patterns between males and females (11, 12, 13, 14). The
CYP story is rather complex, however, because pulsatile GH induces some
but suppresses other CYP genes, and continuous GH induces some and
suppresses other CYP family genes, whereas others are unaffected by
GH.
One of the most consistent observations in regulation of sexually
dimorphic hepatic genes by the GH secretory pattern is involvement of
the signal transducer and activator of transcription (STAT) 5b as a
mediator. Pulsatile GH activates STATs 5a and 5b (15, 16)
and, for example, determines the activation of the male-specific enzyme
CYP2C11 (11, 12). Conversely, continuous GH induces
CYP2C12 expression in females (as well as suppressing CYP2C11)
(12), and induces low-level STAT 5a and 5b activation
(17). Other male-specific CYP genes, but not all, are
reported to be regulated by STAT5 (18, 19). In addition,
the male-specific hepatic expression of the sex limited protein
(C4-slp) gene is also determined by male GH secretion (20, 21), and utilizes STAT5 (22). Analysis of mice
deficient in STAT5b showed that male-specific liver gene expression
(major urinary proteins and various CYP genes) decreased to female
levels and that female-specific liver gene products were increased.
Body growth rate in STAT5b-deficient males was reduced to wild-type
female levels. Thus, loss of STAT 5b is associated with loss of sexual
dimorphism of body growth rates and liver gene expression
(23). Disruption of the STAT 5a gene did not impair
hepatic male-specific gene expression, while in female mice loss of
STAT 5a or STAT 5b similarly increased hepatic expression of
female-specific genes (24). Mice deficient in both STAT 5a
and 5b also showed impairment of male-specific hepatic gene expression
as observed in STAT 5b knockouts, and loss of male-specific body growth
rate (25). Thus STAT 5b appears to be a major determinant
of sexual dimorphism of hepatic gene expression and body growth, which
is determined by pulsatile vs. continuous GH secretion
patterns characteristic of male vs. female rodents,
respectively.
An elegant link in establishing physiological relevance of STAT5
activation in direct relation to spontaneous, endogenous GH pulses in
males and females has recently been provided by the laboratories of
Tannenbaum and of Waxman, as presented in this issue of
Endocrinology (25A ). Correspondence of levels
of liver STAT5 binding activity with spontaneous episodes of endogenous
GH secretion was shown in individual freely moving adult male and
female rats. In males, the highest STAT5 binding activity was observed
during the initial phase, on the upswing or at a peak of GH secretion,
and the lowest activity at troughs, with intermediate STAT5 binding
measured during the downswing of GH pulses. In females, the STAT5
binding activity during the initial phase of a GH secretory episode was
lower than in males, corresponding with lower GH levels, and during the
trough was similar to the baseline in males. The results of these
studies of relatively simple design, using a well characterized but
elaborate animal model in conjunction with a standard test of hepatic
STAT5 binding activity, provide support that STAT5 binding activity is
temporally related to spontaneously occurring GH pulses under
physiological conditions. Emerging from these observations are
implications that GH signaling and consequent regulation of expression
of at least some genes using STAT5 may also be pulsatile.
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Implications for GH Signaling
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An accepted model of GH action involves GH binding to dimerized GH
receptors (GHRs), leading to activation of the GHR-associated tyrosine
kinase JAK2 and tyrosyl phosphorylation of JAK2 and GHR. Among the
downstream consequences is tyrosyl phosphorylation of STAT5a and 5b,
leading to STAT5 dimerization, translocation to the nucleus and binding
to DNA of GH-responsive genes at GAS or GAS-like elements
(26). An implication of the observations of Tannenbaum
et al. (25A ) that spontaneous GH episodes
elicit corresponding changes in STAT5 binding activity, which are rapid
and transient, is that the signaling events between the association of
GH with its receptor and "episodes" of STAT5 activation are
coordinately pulsatile. This allows the system to maintain high
sensitivity to rapidly changing GH levels.
Pulsatility of STAT activation via rapid on/off of GH signaling is
indeed one of the main inferences drawn by the authors, who state that
liver STAT5 is repeatedly activated by successive, spontaneous GH
secretory episodes, and that time-dependent down-regulation of GH
signaling to hepatic STAT5 begins after the initial phase of a GH
secretory episode. These suggestions are consistent with the rapid and
transient nature of the stimulation by GH of JAK2 activation, GHR
phosphorylation, and tyrosyl phosphorylation of STATs 5a and 5b
(27) and with observations from other model systems.
Hypophysectomized rats, or GH-responsive cells, treated with GH in a
pulsatile or continuous manner have been used to demonstrate the time
dependence of STAT5 binding and STAT 5b phosphorylation, including a
2-h refractory period following STAT5 activation (16) and
time dependence of STAT5 translocation (15). For example,
intermittent pulses of GH in hypophysectomized rats triggered repeated
phosphorylation of hepatic STAT5, and continuous GH led to a decrease
in STAT5 phosphorylation. The lower level of STAT5b activation in
female rats may reflect increased activity of phosphotyrosine
phosphatases toward GHR, JAK2 and STAT5b (28).
Because earlier work using in vivo and in vitro
models of GH secretion patterns is consistent with the results of the
Tannenbaum et al. (25A ) study analyzing
endogenous spontaneous GH pulses in rats under physiological
conditions, then observations of rapid activation and down-regulation
of GH signaling events leading to STAT5 binding, also derived from the
model systems, are likely to pertain to the consequences of endogenous
GH pulses. If so, individual endogenous GH pulses would initiate
repeated activation of GH signaling events leading to increased STAT5
binding to DNA, followed by rapid decline in these events. Earlier
studies also indicate that a refractory period following each peak
coincides with the interval until the next spontaneous secretory
episode. Tannenbaum et al. (25A ) suggest that
such periodicity involves shuttling STAT5 repeatedly from cytoplasm to
nucleus and back every 3–3.5 h. Mechanisms for STAT5 translocation and
its regulation are currently under study but are not clearly understood
(29). Other factors that might contribute to possible
pulsatility in GH signaling to STAT5 are rates of GHR recycling
(30) and mechanisms for attenuating/turning off activated
signaling events, including JAK2 activation and inactivation, and
phosphotyrosine phosphatases (30A 30B ). Consistent with
rapid reduction in signaling to STAT5 are observations that members of
the GH-inducible suppressor of cytokine signaling (SOCS)/cytokine
inducible SH2 protein (CIS) family can inhibit GH-stimulated
activation of STAT5b and STAT5-dependent transcriptional activation,
using various mechanisms including direct JAK2 kinase inhibition or
modulation of GHR tyrosine phosphorylation at specific sites (31 31A ). Given the complexity of endogenous GH secretory patterns
(and their lability in altered physiological conditions) for either
males or females, and the many regulatable components involved in GH
signaling between its receptor and STAT5, it is most likely that if GH
signaling events are episodic under physiological conditions, multiple
regulatory events are involved, some of which may confer pulsatility in
the cell and in the organism.
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Implications for Gene Transcription
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The observations of Tannenbaum et al.
(25A ) demonstrate intermediate STAT5 binding activity in
livers from female rats exposed to intermediate levels of circulating
GH during its relatively continuous secretion pattern, compared with
males. An important follow-up is to determine whether quantitative
differences in STAT5 binding activity lead to differences in
transcriptional activation of female-specific or male-specific genes.
Other determinants of the specificity by which STAT5a or STAT5b
participate in transcriptional activation of sexually dimorphic genes
must also be elucidated. For example, STAT 5a and 5b are implicated in
regulation of many genes, not just those that are expressed in a
sexually dimorphic manner or in response to GH. Among other
GH-regulated hepatic genes that use STAT5 are those encoding the liver
specific serine protease inhibitor Spi2.1 (32, 33, 34), the
acid-labile subunit (ALS) that forms a complex with IGF-1 and
IGF-binding proteins in the circulation (35), and most
recently identified, IGF-1 itself (36). The fact that
STAT5 regulates a variety of genes in different ways indicates that
there are multiple determinants in addition to STAT5 that contribute to
regulation of these genes, because only some appear to be responsive to
the GH secretory pattern. Differences in formation of STAT 5a/b
heterodimers vs. homodimers were suggested as one type of
determinant of male- or female-specific gene expression, based on
studies of STAT5a knockout mice (24). It is also of note
that STAT5a and 5b have been reported to inhibit PRL induction of the
gene for interferon regulatory factor-1, while they mediate
PRL-stimulated expression of the ß casein gene promoter
(37), indicating that STAT5a and 5b can serve as a
positive or negative regulators of gene transcription. It is thus
possible that reciprocal roles of STAT5 in stimulating and inhibiting
activation of different genes contribute to their influences on
sexually dimorphic gene expression.
It is now well established that transcription factors, including STAT
5a and 5b, participate in complexes with other DNA-binding or nuclear
proteins to mediate changes in gene transcription. Among such
interactions, glucocorticoid receptor enhances STAT5 transactivation
potential (38), and association of STAT5 with the
coactivator p300 is an important contributor to activation of the ß
casein gene (39). It should be noted that various reports
indicate that factors other than STAT5 contribute to GH-regulated
transcription of CYP genes (40, 41). Thus it is
conceivable that interactions of STAT5b or STAT5a with other nuclear
proteins also determine whether transcription of sexually dimorphic
genes occurs when STAT5 is bound.
Another system in which frequency-dependent pulses of a hormone
determine differential transcription of target genes has been described
for regulation by GnRH of gonadotropin subunit genes (42, 43). The 
-subunit gene is stimulated by rapid to intermediate
GnRH pulses, whereas the LH ß-subunit gene responds to intermediate
GnRH pulses and the FSH ß-subunit gene to longer interval pulses. It
has recently been shown that unique composite response elements and
transcription factors on the LH-ß subunit gene are responsible for
GnRH stimulation and may contribute to the differential responses to
GnRH pulses (44). Further, distinct response elements that
mediate GnRH stimulation of the LH ß-subunit gene are regulated by
different signaling pathways (45). These observations
highlight that multiple factors contribute to regulation of gene
transcription by pulsatile hormone secretion. Thus, although regulation
of sexually dimorphic genes by the pulsatile male GH secretion pattern
is likely to involve STAT5b, other DNA sequences, other transcription
factors, and other signaling mechanisms may contribute to such
regulation and determine specificity for one gene compared with
another. As straightforward as the findings of Tannenbaum et
al. (25A ) seem in showing direct links between
spontaneous GH secretion patterns and hepatic STAT5 binding to DNA in
male and female rats under physiological conditions, these studies
provide insight into what may represent only a portion of the factors
that contribute to regulation of STAT5 dependent genes by endogenous GH
secretion patterns. Further, it should be recognized that regulation of
some genes (e.g. c-fos) by GH appears to be
independent of STAT5a or 5b, indicating that STAT5a and 5b do not
account for all of the biological effects of GH.
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Complexities of Timing in GH Action
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Issues of timing have consistently been critical factors in GH
action. The paper by Tannenbaum et al. emphasizes how
specific timing in endogenous GH secretory patterns determines
STAT5-dependent events that contribute to regulation of male- or
female-specific hepatic genes. Integration of time and level of peak
height and nadir, as well as peak and trough duration, are reflected in
STAT5 binding and presumably STAT5-dependent gene expression. Many
earlier studies demonstrated the importance of timing for a variety of
GH responses because acute and chronic GH exposure were found to result
in opposite metabolic responses in target tissues: an initial exposure
to GH produces acute insulin-like changes such as stimulation of
glucose transport or antilipolysis in fat or stimulation of amino acid
uptake in muscle, whereas chronic GH produces the opposite, or
antiinsulin changes in metabolism (46, 47). Further, the
acute response to GH was typically followed by a period of
refractoriness to that effect of GH. The physiological importance of
these time-dependent responses to GH remains elusive, and how they
relate to GH secretion patterns, if at all, is not known. As
physiological studies such as that of Tannenbaum et al.
(25A ) continue in the context of our increasing
understanding of GH signaling and actions, it is likely that we shall
come to understand more of the importance of timing of GH secretion and
activation of target tissues in serving as a code that determines at
least some biological responses to GH. It will be of interest to
establish whether GH secretion patterns are closely associated with
STAT5 in humans as well, and how such associations contribute to GH
physiology and pathophysiology.
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Acknowledgments
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Footnotes
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Abbreviations: CYP, Cytochrome P450; GHRs, GH receptors; STAT,
signal transducer and activator of transcription.
Received September 10, 2001.
Accepted for publication September 10, 2001.
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Physiology of Episodic GH...
Implications for GH Signaling