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Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430
Address all correspondence and requests for reprints to: Dr. Douglas Stocco, Department of Cell Biology and Biochemistry, Texas Tech University Health Science Center, 3601 4th Street, 5B108 HSC Building, Lubbock, Texas 79430. E-mail: doug.stocco{at}ttmc.ttuhsc.edu
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 TOP ABSTRACT INTRODUCTIONTHE CASE FOR StAR...TRANCRIPTIONAL REGULATION OF THE...HOW DOES StAR MEDIATE...REFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTHE CASE FOR StAR...TRANCRIPTIONAL REGULATION OF THE...HOW DOES StAR MEDIATE...REFERENCES |
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THE CASE FOR StAR AS THE ACUTE REGULATOR |
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TOPABSTRACTINTRODUCTIONTHE CASE FOR StAR...TRANCRIPTIONAL REGULATION OF THE...HOW DOES StAR MEDIATE...REFERENCES |
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However, the observation that provided the most compelling evidence for the essential requirement for StAR in steroidogenesis came with the finding that mutations in the StAR gene were the cause of the potentially lethal condition known as congenital lipoid adrenal hyperplasia (lipoid CAH) (25). Patients with this disease are unable to synthesize adequate amounts of steroids, are characterized by excessive levels of cholesterol and cholesterol esters in adrenal and testicular steroidogenic cells, and will not survive unless appropriate steroid replacement therapy is quickly administered. The events involved in the pathogenesis of lipoid CAH were further elucidated with the description of the two-hit model. This model hypothesized an initial loss in steroidogenesis due to mutations in StAR followed by a subsequent and complete loss of steroidogenesis due to the damage caused by the accumulation of cholesterol esters in the cell (26). The case for StAR playing an essential role in regulated steroid synthesis was greatly bolstered when StAR-specific knockout mice were generated and found to have a phenotype that was essentially identical to the human condition (27). Thus, biochemical and genetic studies converged to demonstrate an indispensable role for StAR in steroid hormone biosynthesis in adrenal and gonadal tissues.
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TRANCRIPTIONAL REGULATION OF THE StAR GENE |
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StAR expression can be regulated both positively and negatively by agents that presumably act on its promoter. Studies to determine which regulatory elements were present within the StAR promoter and the manner in which transcription factors and other proteins interact with these elements were conducted. In early studies it was demonstrated that hormone-stimulated steroid synthesis was accompanied by a rapid increase in StAR mRNA levels (32). Since trophic hormone stimulation usually results in a rapid increase in intracellular cAMP, the role of cAMP in the regulation of StAR was investigated and found to have a positive and rapid effect (33, 34, 35, 36, 37, 38). Most studies demonstrated that the cAMP-responsive site was found within the first 254 nucleotides relative to the transcription start site (33, 35, 36, 37, 38), and this region has been the focus of studies to identify promoter elements and their cognate-binding proteins that mediate the cAMP response. However, the StAR promoter lacks a consensus full cAMP response element, raising the possibility that the cAMP response element binding protein might not act directly on sequences found in the StAR promoter.
Steroidogenic factor 1 (SF-1), was the first transcription factor to be studied as a potential regulator of the StAR gene. Several SF-1 consensus binding sites have been identified in the StAR promoter (35, 37, 38). Two of these sites, located at positions -97 and -42, are highly conserved in several species whose promoter regions have been sequenced, whereas the -132 site may only be present in mouse and rat. Utilizing transient transfection protocols, SF-1 has been demonstrated to transactivate the StAR promoter in several cell types (35, 36, 37, 38). It is also possible that SF-1 may play some role in the developmental regulation of the StAR gene since StAR mRNA is not detected in the urogenital ridge of the SF-1 knockout mouse during embryonic development (32).
While SF-1 plays a role in the regulation of the StAR gene, it
became apparent that other elements were also involved in StAR’s
tissue and temporal specific expression. The CCAAT/enhancer binding
proteins (C/EBPs) are a family of basic region/leucine zipper
transcription factors implicated as regulators of differentiation and
function in multiple cell types (39). Previous studies
have demonstrated that two family members, C/EBP
and C/EBPß, are
expressed in steroidogenic cells, including Leydig cells and ovarian
granulosa cells (40, 41). Two putative C/EBP binding sites
in the StAR promoter have been identified (42, 43, 44). These
studies have determined that the StAR promoter is transactivated by
C/EBPß during transient transfection assays and that SF-1
transactivation of the StAR promoter is dependent on the presence of
functional C/EBP binding sites, suggesting that SF-1 and C/EBPß form
a complex on this promoter (42, 43). In other studies,
functional assays of the StAR promoter were performed using FSH-induced
primary granulosa cell cultures from prepubertal rat ovaries
(43). This led to the identification of two
trans-acting proteins, C/EBPß and GATA-4, which were
required for the transcriptional activation of the StAR promoter. This
study revealed a non-consensus binding sequence for C/EBPß
(-81/-72), located 10 nucleotides upstream from a consensus motif for
GATA-4 binding (-61/-66). Site-directed mutagenesis reinforced the
observation that these two binding elements are required for
transactivation of the StAR promoter in these cells. Western analyses
demonstrated that while GATA-4 was constitutively expressed in
granulosa cells, the C/EBPß isoforms were induced by FSH. This
suggests that GATA-4 may play a permissive role and C/EBPß may play a
regulated role in the acute rate of StAR transcription.
Findings from other laboratories have demonstrated that the sterol regulatory element binding protein-1a (SREBP-1a) may also be involved in the regulation of the StAR gene (45, 46). These studies have demonstrated the presence of potential sterol regulatory element binding sites in both the human and the rat StAR promoters and have demonstrated that SREBP-1a is capable of transactivating the StAR promoter. They further indicated that other transcription factors such as SF-1, nuclear factor-Y, yin yang 1, and Sp1 may also be involved in the action of SREBP1a on the StAR promoter. Since the SREBP family of transcription factors are involved in the up-regulation of proteins involved in steroid biosynthesis and the uptake of cholesterol, it is intriguing to speculate that StAR may be coordinately regulated by SREBP-1a along with these other steroidogenesis-supporting proteins.
In summary, it is has been determined that several currently identified transcription regulatory elements and their binding sequences are involved in the up-regulation of the StAR gene. However, it is also possible that additional regulatory elements will continue to be uncovered as it is clear that the regulation of the StAR gene is complex. In this regard, studies in our laboratory have indicated that CREB can also bind to and transactivate the StAR promoter and can do so in a rapid manner (in review). The major challenge in this area will be to determine how the different promoter sequences and their cognate binding factors interact with each other to bring about the rapid expression of the StAR gene.
Negative Regulation of the StAR gene
Interestingly, the StAR promoter may also harbor elements involved
in repression of its transcription. DAX-1 (dosage-sensitive sex
reversal, adrenal hypoplasia congenita, critical region on the X, gene
1) is an unusual member of the nuclear hormone receptor family,
retaining homology with only the ligand-binding domain of the nuclear
hormone receptors (47). The DNA-binding domain lacks zinc
finger motifs and consists of a repeat of a 65- to 67-amino acid
sequence in its N terminus (47). DAX-1 overexpression was
demonstrated to inhibit the synthesis of steroids in Y-1 mouse adrenal
tumor cells (48). Indeed, the DAX-1 protein has been
demonstrated to contain a powerful transcriptional silencing domain in
its C-terminal region (49). As a possible mechanism of
action for this observation, DAX-1 has been shown to interact directly
with a hairpin structure in the StAR promoter to inhibit its expression
in one study (48) and to bind directly to SF-1, resulting
in an inhibition of SF-1-mediated transactivation in another study
(50). Combined, these data implicate DAX-1 as a key factor
in the regulation of StAR gene expression.
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HOW DOES StAR MEDIATE CHOLESTEROL TRANSFER? |
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At the time the above experiments were being performed, information on the mechanism by which StAR mediated cholesterol transfer to the inner mitochondrial membrane was indeed scarce. In one effort to explain StAR action, Kallen et al. (59) demonstrated that StAR can act as a sterol transfer protein and that the function of the StAR protein may be to enhance desorption of cholesterol from one sterol-containing membrane to another. In this model, StAR is specifically directed to the mitochondria via its N terminus and, upon its arrival at the outer mitochondrial membrane, the C terminus produces alterations in this membrane that in some manner result in the transfer of cholesterol from the outer to the inner membrane. Interestingly, the transfer of cholesterol to both trypsin-treated and heat-treated mitochondria or to heat-treated microsomes by purified StAR protein was specific in that identical experiments employing phosphatidylcholine failed to show transfer of this phospholipid. This is particularly pertinent to the situation found in steroidogenic mitochondria in which the desorption of cholesterol from the sterol-rich outer membrane to the sterol-poor inner membrane (60) would serve to enhance pregnenolone synthesis by the P450scc enzyme. While indicating that StAR had this capability, this study, however, failed to provide a molecular mechanism of how StAR could act as a sterol carrier protein.
The Molten Globule Hypothesis
Another approach was taken by Miller and colleagues
(61) in which they attempted to determine the physical
characteristics of the StAR protein under different physico-chemical
conditions and then utilize these characteristics to provide insights
into the mechanism of StAR action. In one of their studies they
subjected StAR to limited proteolysis at different pH values and found
that the molecule behaves differently as the pH decreases. They
demonstrated that at pH values in the 3.5–4.0 range StAR undergoes
conformational changes that result in a partial unfolding of the
protein and a transition to a molten globule state. Molten globules are
structures within proteins that have lost at least some of their
tertiary structure but which have retained virtually all of their
secondary structure. They speculated that if the pH microenvironment
surrounding the mitochondria is acidic, which might be caused by the
expulsion of protons from the mitochondrial matrix by the proton pump
and/or by the presence of the negatively charged head groups of the
phospholipids in the outer mitochondrial membrane, the StAR molecule
may undergo a conformational shift. They further hypothesized that as
the transition to a molten globule occurs, this structural change could
result in an opening of the StAR protein, possibly exposing a
hydrophobic region, or it may prolong the interval with which StAR can
reside on the outer membrane, thus allowing increased transfer of
cholesterol during this period.
With the demonstration 1) that StAR was fully active even without its signal sequence, 2) that it could act as a sterol carrier protein, and 3) that it could form a molten globule while interacting with the mitochondrial outer membrane, a picture began to emerge in which StAR might be causing perturbations of the outer membrane that resulted in cholesterol movement from the outer to the inner mitochondrial membrane. An obvious possibility was that StAR was interacting with other mitochondrial outer membrane proteins and/or phospholipids to produce this effect. However, attempts to identify such binding partners using the yeast two-hybrid system, coimmunoprecipitation, and binding assays utilizing radioactive StAR and isolated mitochondria have thus far failed to produce any components that specifically interact with StAR (62). The methods used to identify StAR binding partners can be technically difficult and subject to artifacts. However, to date they have produced no positive results. In support of these findings it was demonstrated that StAR could promote cholesterol transfer to mitochondria in which the outer membrane proteins have been removed by partial proteolysis with trypsin (59). This would suggest that StAR does not have protein binding partners on the outer mitochondrial membrane and can, instead, interact directly with membrane phospholipids. A recent study using fluorescence energy transfer has demonstrated that StAR and the peripheral benzodiazepine receptor (PBR) are closely associated on the outer mitochondrial membrane, being less than 100 A from each other (63). PBR is a membrane protein found in high abundance in the outer mitochondrial membrane of steroidogenic cells and has been shown to be involved in cholesterol delivery to the inner mitochondrial membrane (64). Based on this association, the authors proposed a model in which StAR targets cholesterol to the PBR, which then facilitates its transfer to the inner mitochondrial membrane. While PBR appears to be involved in cholesterol transfer to the inner mitochondrial membrane, little is known concerning the mechanism of its action in this process, and, in any event, it appears that StAR can transfer cholesterol into the mitochondria in the absence of outer mitochondrial membrane proteins (59).
StAR-Related Lipid Transfer (START) Domains
As indicated earlier, the cholesterol-transferring region of the
StAR protein appears to be located in the C-terminal region of the
protein as demonstrated in studies with both N-terminally truncated
StAR proteins and MLN64. A hint of how the C terminus of these proteins
might transfer cholesterol has recently been put forth by Ponting and
Aravind (65), who demonstrated that sequences in the
C-terminus of StAR are homologous to sequences in several other
proteins, including MNL64, which display diverse functions. They named
these sequences START domains, for StAR-related lipid transfer domains.
START domains consist of approximately 200–210 amino acid stretches,
and the significance of these domains is that they are capable of
binding lipids. Thus, with this information, the possibility that StAR
was a lipid-binding carrier protein would have to be considered. This
possibility received an exciting boost recently when Tsujishita and
Hurley (66) succeeded in obtaining crystals and solving
the structure for the START domain of the MNL64 protein. Because of
problems in purifying and crystallizing the START domain from StAR,
they focused on the START domain of MLN64, which shows the highest
degree of homology to the StAR-START domain and found that it readily
crystallized. They demonstrated that both StAR-START and MLN64-START
could bind cholesterol in an essentially identical manner and that
binding occurred in a ratio of 1:1. These studies were important in
that they demonstrated that the START domains of both MLN64 and StAR
behaved similarly and, thus, were a confirmation of earlier studies
that had been performed in vitro using transfected cells
(26, 57). The crystal structure of the MLN64-START at 2.2
Å indicated that it consisted of an + ß fold built around a
U-shaped incomplete ß-barrel. MLN64-START contains a nine-stranded
antiparallel ß-sheet, four -helices, and two 
-loops. Most
importantly, the tertiary structure of MLN64-START revealed a
hydrophobic tunnel that was 26 x 12 x 11 Å in size and was
large enough to bind a single molecule of cholesterol. Interestingly,
when three of the most common mutations resulting in lipoid CAH are
projected onto the MLN64-START domain model, they are all found to
reside quite close to each other, and two of these mutations reside
within the cholesterol-binding hydrophobic tunnel. These mutations
would be expected to disrupt the structure of the tunnel and quite
likely result in a decrease in cholesterol binding. Based on these
findings, the authors propose that StAR functions in transferring
cholesterol to the inner mitochondrial membrane via its ability to bind
and function as an intermitochondrial membrane cholesterol-shuttling
protein. However, several aspects of this model are in conflict with
observations that have been made previously and with some hypotheses of
other models that have been proposed. These conflicts will be discussed
later.
Probing the Physical Characteristics of StAR
While the controversy continues of whether StAR can act as a
cholesterol-shuttling protein in the intermembrane space or whether it
can act on the outer mitochondrial membrane to effect cholesterol
transfer, the Miller laboratory has continued to add new
structure-function studies to the field. In one study they examined the
structural properties of a bacterially produced segment of the StAR
protein corresponding to amino acids 63–193, the protease-resistant
region (67). They found that expression of the 63–193
domain in the absence of the molten globule 194–285 domain altered its
structure, rendering it more susceptible to protease digestion and
devoid of tertiary structure. Treatment with detergents increased the
secondary structure of this domain, indicating that, like the 194–285
domain, the 63–193 domain could also form a molten globule. Most
importantly, addition of 63–193 StAR to liposomes consisting of
phosphatidylcholine or phosphatidylserine induced the formation of
stable protein-liposome complexes. These data indicate the N-terminal
region of the StAR protein can form a molten globule and that this
structure can interact directly with membranes. This finding is
important since, when in the molten globule state, proteins lose
tertiary structure and can open, thus exposing a hydrophobic interior
(if one exists), allowing them to interact with phospholipid
membranes. The strong interaction of water-soluble proteins with
phospholipid membranes after their transition to molten globule states
has been well documented previously (68, 69, 70, 71, 72), and thus a
case for StAR interaction with a phospholipid environment can be made.
This observation has important implications in that StAR has been shown
to closely interact with the outer mitochondrial membrane during the
course of cholesterol transfer, and this interaction apparently does
not require that it bind to other proteins (59).
These observations were followed by more extensive studies on StAR and its interactions with artificial membranes. Utilizing unilamellar artificial membranes composed of phosphatidylcholine or phosphatidylcholine:cholesterol (73), Miller’s group demonstrated that recombinant StAR can readily bind to these membranes in the complete absence of other proteins, supporting the hypothesis that StAR can interact directly with the outer mitochondrial membrane, and does not require a receptor protein. Also, this binding occurred maximally at low pH, conditions favoring the formation of molten globule structures. While the degree of binding of StAR to these membranes varied with the heterogeneity of the membrane composition, a most interesting observation was that StAR was able to bind preferentially to the cholesterol-rich domains in cholesterol-containing membranes. Cholesterol-rich domains have been previously demonstrated in biological membranes (74), and it is intriguing to speculate that StAR binds to such regions in the relatively cholesterol-rich mitochondrial outer membrane to more easily facilitate transfer of this substrate to the cholesterol-poor inner membrane. Importantly, StAR proteins harboring mutations that cause lipoid CAH, and thus impaired steroidogenesis, did not bind to the artificial membranes as efficiently as did wild-type StAR (74). They also found that when StAR bound to artificial membranes containing cardiolipin in concentrations approximating that found in authentic mitochondrial outer membranes, it underwent a conformational change to a molten globule more readily than when cardiolipin-free membranes were used.
THE ARGUMENTS
It is eminently clear at this point in time that we do not know
precisely how StAR works to mediate cholesterol transfer to the inner
mitochondrial membrane. Many of the observations that have been made to
date cannot be disputed, but they also do not tell us how StAR works.
For example, the data that StAR can act as a sterol carrier protein and
promote desorption from one membrane to another is most convincing, but
is not placed within the context of what is occurring in a
steroidogenic cell. Also, the observation that StAR and PBR are in
close proximity to each other on the outer mitochondrial membrane is
very convincing but does not tell us if they act together to promote
cholesterol transfer. In fact, it is hard to imagine that StAR would
target cholesterol to the outer mitochondrial membrane where PBR would
transfer it to the inner membrane. First, if it performs this function
via its cholesterol recognition/interaction amino acid sequence and
consensus pattern (CRAC) sequence, that is known to bind cholesterol,
then N-62 StAR should be completely inactive since the CRAC domain in
StAR is found at positions 5–18 in the N terminus (75).
This is not the case as many studies have shown N-62 to be fully active
in steroidogenesis when transfected into various cell lines, and one
study even demonstrated that N-62 StAR could transfer cholesterol to
membranes of isolated mitochondria (59). Second, if it
delivers cholesterol to the PBR for subsequent transfer via its
hydrophobic cholesterol binding START domain, it is most difficult to
imagine that it could perform this task up to 400 times per molecule of
StAR, as calculated by Jefcoate et al. (76),
before being taken up by the mitochondria. From yet another point of
view, it seems unlikely that StAR functions as a cytosolic cholesterol
carrier protein in that virtually every study on StAR has found it to
be tightly associated with, and rapidly taken up by, the mitochondria
after its synthesis.
The two models that would appear to have the most credence at this time are the intermembrane shuttle model and the molten globule model. In the former, StAR acts as a carrier of cholesterol from the outer to the inner mitochondrial membrane, and in the latter StAR acts to promote cholesterol transfer via changes in its conformation that might produce a hydrophobic tunnel or region through which cholesterol might pass. Each model has strong points and each model has facets that appear to be incompatible with the other. For example, the cholesterol shuttle model is inconsistent with the observation that StAR can act on the outer mitochondrial membrane and promote cholesterol transfer without ever entering the intermembrane space or matrix. There may also be some problems with stoichiometry with this model in that StAR appears to become inactivated very quickly, and it does not appear that transferring one cholesterol molecule at a time would account for the large number of steroid molecules that are formed. Also, the openings of the hydrophobic core of the START domain do not appear to be large enough to allow cholesterol molecules to enter or exit the pocket without some sort of conformational change in the protein. It is highly speculative, but interesting, that perhaps the transformation of the START domain to something approximating a molten globule would allow for the opening of the hydrophobic core and thus cholesterol could enter and exit the tunnel more readily. As for the molten globule hypothesis, the data clearly indicate that StAR can form this structure at low pH. The questions that arise from this model are several. Does the local pH in the vicinity of the outer mitochondrial membrane reach the pH required (3.0–4.0) to form a molten globule? In support of this model it is argued that between the charged head groups of the membrane phospholipids and the extrusion of protons by the proton pump, an acidic environment is produced, but no evidence is available to what this pH actually is in vivo. This model however, is in agreement with observations that an active electrochemical force, in which protons would be actively extruded from the matrix, is required for the support of steroid hormone synthesis (77). In addition, the shuttle model argues that it is not reasonable to hypothesize that a molecule that has evolved such a highly ordered three-dimensional cholesterol-binding pocket would function by eliminating the structure of this pocket through the formation of a molten globule. This argument makes sense, but it is clearly teleological in nature.
Perhaps there is some common ground in these two theories. Miller’s
group (73) has recently stated that their fluorescence
energy transfer data are compatible with StAR acting either on the
outer mitochondrial membrane or in the intermembrane space. If N-62
StAR can indeed act in the intermembrane space, perhaps a fusion of the
two models is possible. One can envision StAR coming into contact with
the mitochondria and, as supported by observations with artificial
membranes, the StAR-START segment of the molecule becomes buried in the
outer mitochondria membrane. Simultaneously, this buried segment of the
StAR protein becomes transformed to a molten globule by the low pH of
the membrane environment. Then, if StAR can traverse the outer membrane
and appear at the intermembrane space, it is possible that it does so
with the hydrophobic cholesterol-binding interior of the StAR-START
domain partially open. This would allow for the rapid binding and
release of cholesterol located in the outer membrane, perhaps by
desorption, to the inner membrane. Thus, the START domain of StAR may
act like a tunnel through which cholesterol can enter at one end and
exit at the other. While this is occurring, the N-terminal domain of
StAR is interacting with a mitochondrial import complex, and eventually
the entire StAR molecule enters the matrix where it is no longer active
in further cholesterol transfer (see Fig. 1
.) Thus, the hydrophobic core,
consisting of a partially opened START domain, is the conduit for
cholesterol transfer for the length of time that is required for StAR
to be imported into the matrix. It is possible that this transfer could
occur in locations in the membranes where contact sites have formed.
For example, if the N terminus of the StAR protein is being imported
simultaneously, the START domain could utilize the contact sites formed
by the import of the N terminus for cholesterol transfer. Such contact
sites have been characterized in steroidogenic cells and have been
shown to contain higher levels of cholesterol (55, 78),
StAR (78), and the first two enzymes in the
steroidogenic pathway, cytochrome P450scc and 3ß-hydroxysteroid
dehydrogenase (78).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: CAH, congenital adrenal hyperplasia; C/EBP, CCAAT/enhancer binding protein; CRAC, cholesterol recognition/interaction amino acid sequence and consensus; DAX-1, dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X, gene 1; P450scc, cytochrome P450 side-chain cleavage enzyme; PBR, peripheral benzodiazepine receptor; SF-1, steroidogenic factor-1; SREBP, sterol regulatory element binding protein-1a; START, StAR-related lipid transfer.
Received for publication April 5, 2001. Accepted for publication June 4, 2001.
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TOPABSTRACTINTRODUCTIONTHE CASE FOR StAR...TRANCRIPTIONAL REGULATION OF THE...HOW DOES StAR MEDIATE...REFERENCES |
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-lactalbumin bound to model membranes. J Biol Chem 270:29910–29915This article has been cited by other articles:
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V. K. Yadav and R. Medhamurthy Dynamic Changes in Mitogen-Activated Protein Kinase (MAPK) Activities in the Corpus Luteum of the Bonnet Monkey (Macaca radiata) during Development, Induced Luteolysis, and Simulated Early Pregnancy: A Role for p38 MAPK in the Regulation of Luteal Function Endocrinology, April 1, 2006; 147(4): 2018 - 2027. [Abstract] [Full Text] [PDF]
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