Molecular mechanisms of insulin-like growth factor-I mediated regulation of the steroidogenic acute regulatory protein in mouse leydig cells.

Growth factors are known to play diverse roles in steroidogenesis, a process regulated by the mitochondrial steroidogenic acute regulatory (StAR) protein. The mechanism of action of one such growth factor, IGF-I, was investigated in mouse Leydig tumor (mLTC-1) cells to determine its potential role in the regulation of StAR expression. mLTC-1 cells treated with IGF-I demonstrated temporal and concentration-dependent increases in StAR expression and steroid synthesis. However, IGF-I had no effect on cytochrome P450 side-chain cleavage or 3beta-hydroxysteroid dehydrogenase protein levels. IGF-I was capable of augmenting N,O'-dibutyrl-cAMP-stimulated steroidogenic responsiveness in these cells. The steroidogenic potential of IGF-I was also confirmed in primary cultures of isolated mouse Leydig cells. IGF-I increased phosphorylation of ERK1/2, an event inhibited by the MAPK/ERK inhibitors, PD98059 and U0126. Interestingly, inhibition of ERK activity enhanced IGF-I-mediated StAR protein expression, but phosphorylation of StAR was undetectable, an observation in contrast to that seen with N,O'-dibutyrl-cAMP signaling. Further studies demonstrated that these events were tightly correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 and scavenger receptor class B type 1. Whereas both protein kinase A and protein kinase C signaling were involved in the IGF-I-mediated steroidogenic response, the majority of the effects of IGF-I were found to be mediated by the protein kinase C pathway. Transcriptional activation of the StAR gene by IGF-I was influenced by several transcription factors, its up-regulation being dependent on phosphorylation of the cAMP response element-binding protein (CREB) and the activator protein 1 family member, c-Jun. Conversely, StAR gene transcription was markedly inhibited by expression of nonphosphorylatable CREB (Ser(133)Ala), dominant negative A-CREB, and dominant negative c-Jun (TAM-67) mutants. Collectively, the present studies identify molecular events in IGF-I signaling that may influence testicular growth, development, and the Leydig cell steroidogenic machinery through autocrine/paracrine regulation.

[1]  I. Huhtaniemi,et al.  Detection of hCG Responsive Expression of the Steroidogenic Acute Regulatory Protein in Mouse Leydig Cells , 2004, Biological Procedures Online.

[2]  Deli Wang,et al.  Upregulation of human chorionic gonadotrophin-induced steroidogenic acute regulatory protein by insulin-like growth factor-I in rat leydig cells , 1998, Endocrine.

[3]  Y. Jo,et al.  Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. , 2005, Molecular endocrinology.

[4]  Y. Jo,et al.  Involvement of Protein Kinase C and Cyclic Adenosine 3′,5′-Monophosphate-Dependent Kinase in Steroidogenic Acute Regulatory Protein Expression and Steroid Biosynthesis in Leydig Cells1 , 2005, Biology of reproduction.

[5]  K. Miyamoto,et al.  Luteinizing hormone-induced extracellular-signal regulated kinase activation differently modulates progesterone and androstenedione production in bovine theca cells. , 2005, Endocrinology.

[6]  D. Stocco,et al.  Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences. , 2005, Current drug targets. Immune, endocrine and metabolic disorders.

[7]  B. J. Clark,et al.  Cyclic adenosine 3',5'-monophosphate (cAMP) enhances cAMP-responsive element binding (CREB) protein phosphorylation and phospho-CREB interaction with the mouse steroidogenic acute regulatory protein gene promoter. , 2005, Endocrinology.

[8]  Hongwei Xue,et al.  Novel signaling stimulated by arsenite increases cholesterol metabolism through increases in unphosphorylated steroidogenic acute regulatory (StAR) protein , 2005, Molecular and Cellular Endocrinology.

[9]  Y. Jo,et al.  Multiple Signaling Pathways Regulating Steroidogenesis and StAR Expression: More Complicated Than We Thought , 2005 .

[10]  K. Miyamoto,et al.  LH-induced ERK Activation Differently Modulates Progesterone and Androstenedione Production in Bovine Theca Cells. , 2005 .

[11]  P. Crépieux,et al.  Extracellular signal-regulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression. , 2005, Reproduction, nutrition, development.

[12]  Y. Jo,et al.  Regulation of steroidogenesis and steroidogenic acute regulatory protein in R2C cells by DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1). , 2004, Endocrinology.

[13]  O. Söder,et al.  Extracellular signal-regulated kinases are involved in the acute activation of steroidogenesis in immature rat Leydig cells by human chorionic gonadotropin. , 2004, Endocrinology.

[14]  D. B. Hales,et al.  Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR) , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[15]  K. W. Chan,et al.  Low temperature blocks the stimulatory effect of human chorionic gonadotropin on steroidogenic acute regulatory protein mRNA and testosterone production but not cyclic adenosine monophosphate in mouse Leydig tumor cells. , 2004, Metabolism: clinical and experimental.

[16]  Dheer Singh,et al.  Concerted regulation of the porcine steroidogenic acute regulatory protein gene promoter activity by follicle-stimulating hormone and insulin-like growth factor I in granulosa cells involves GATA-4 and CCAAT/enhancer binding protein beta. , 2004, Endocrinology.

[17]  D. Stocco,et al.  Assessment of the role of activator protein-1 on transcription of the mouse steroidogenic acute regulatory protein gene. , 2004, Molecular endocrinology.

[18]  D. B. Hales,et al.  Phosphorylation of the hamster adrenal steroidogenic acute regulatory protein as analyzed by two-dimensional polyacrylamide gel electrophoreses , 2004, Molecular and Cellular Endocrinology.

[19]  D. Stocco,et al.  Involvement of multiple transcription factors in the regulation of steroidogenic acute regulatory protein gene expression , 2003, Steroids.

[20]  M. Hardy,et al.  Effects of insulin-like growth factor I on steroidogenic enzyme expression levels in mouse leydig cells. , 2003, Endocrinology.

[21]  Z. Rosenwaks,et al.  The role of mitogen-activated protein kinase in insulin and insulin-like growth factor I (IGF-I) signaling cascades for progesterone and IGF-binding protein-1 production in human granulosa cells. , 2003, The Journal of clinical endocrinology and metabolism.

[22]  E. Lalli,et al.  Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1. , 2003, Journal of molecular endocrinology.

[23]  R. Seger,et al.  Down-regulation of steroidogenic response to gonadotropins in human and rat preovulatory granulosa cells involves mitogen-activated protein kinase activation and modulation of DAX-1 and steroidogenic factor-1. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  B. Staels,et al.  Regulation of the scavenger receptor BI and the LDL receptor by activators of aldosterone production, angiotensin II and PMA, in the human NCI-H295R adrenocortical cell line. , 2003, Biochimica et biophysica acta.

[25]  K. W. Chan,et al.  Mouse Leydig tumor cells produce C-19 steroids, including testosterone , 2003, Steroids.

[26]  Y. Jo,et al.  Differential Regulation of Steroid Hormone Biosynthesis in R2C and MA-10 Leydig Tumor Cells: Role of SR-B1-Mediated Selective Cholesteryl Ester Transport1 , 2003, Biology of reproduction.

[27]  I. Huhtaniemi,et al.  Mechanisms of Epidermal Growth Factor Signaling: Regulation of Steroid Biosynthesis and the Steroidogenic Acute Regulatory Protein in Mouse Leydig Tumor Cells1 , 2002, Biology of reproduction.

[28]  A. Capponi,et al.  Repression of DAX-1 and Induction of SF-1 Expression , 2002, The Journal of Biological Chemistry.

[29]  J. Tremblay,et al.  Protein kinase A-dependent cooperation between GATA and CCAAT/enhancer-binding protein transcription factors regulates steroidogenic acute regulatory protein promoter activity. , 2002, Endocrinology.

[30]  V. Lingappa,et al.  Rapid regulation of steroidogenesis by mitochondrial protein import , 2002, Nature.

[31]  M. Ascoli,et al.  The lutropin/choriogonadotropin receptor, a 2002 perspective. , 2002, Endocrine reviews.

[32]  C. Wheeler-Jones,et al.  Requirement for Erk1/2 Activation in the Regulation of Progesterone Production in Human Granulosa-lutein Cells Is Stimulus Specific Erk1/2 Activation Was Reduced by Preincubation with Pka Inhibitors, including Myristoylated Pki, Suggesting That Camp Mediates Erk1/2 Activation. Two Structurally Disti , 2022 .

[33]  D. Hales,et al.  Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos , 2002, Molecular and Cellular Endocrinology.

[34]  I. Huhtaniemi,et al.  Synthesis, purification and structural and functional characterization of recombinant form of a common genetic variant of human luteinizing hormone. , 2002, Human Molecular Genetics.

[35]  E. Lalli,et al.  Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. , 2002, Molecular endocrinology.

[36]  Dong Zhao,et al.  Mitochondrial Processing of Newly Synthesized Steroidogenic Acute Regulatory Protein (StAR), but Not Total StAR, Mediates Cholesterol Transfer to Cytochrome P450 Side Chain Cleavage Enzyme in Adrenal Cells* , 2001, The Journal of Biological Chemistry.

[37]  Peter M. Jones,et al.  ERKs Regulate Cyclic AMP-induced Steroid Synthesis through Transcription of the Steroidogenic Acute Regulatory (StAR) Gene* , 2001, The Journal of Biological Chemistry.

[38]  Revital Rosenberg,et al.  The ERK Signaling Cascade Inhibits Gonadotropin-stimulated Steroidogenesis* , 2001, The Journal of Biological Chemistry.

[39]  I. Huhtaniemi,et al.  Biphasic Action of Prolactin in the Regulation of Murine Leydig Tumor Cell Functions* * This study was supported by a research grant from the Sigrid Jusélius Foundation. , 2001, Endocrinology.

[40]  C. Tai,et al.  Role of mitogen-activated protein kinase in prostaglandin f(2alpha) action in human granulosa-luteal cells. , 2001, The Journal of clinical endocrinology and metabolism.

[41]  H. Sasano,et al.  Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. , 2000, Molecular endocrinology.

[42]  D. Stocco,et al.  The Role of Arachidonic Acid in Steroidogenesis and Steroidogenic Acute Regulatory (StAR) Gene and Protein Expression* , 2000, The Journal of Biological Chemistry.

[43]  B. J. Clark,et al.  Steroidogenic Factor-1 Influences Protein-Deoxyribonucleic Acid Interactions within the Cyclic Adenosine 3',5'-Monophosphate-Responsive Regions of the Murine Steroidogenic Acute Regulatory Protein Gene. , 2000, Endocrinology.

[44]  A. Makrigiannakis,et al.  Insulin and insulin-like growth factor-I and -II modulate human granulosa-lutein cell steroidogenesis: enhancement of steroidogenic acute regulatory protein (StAR) expression. , 1999, Molecular human reproduction.

[45]  B. Cooke.  Signal transduction involving cyclic AMP-dependent and cyclic AMP-independent mechanisms in the control of steroidogenesis , 1999, Molecular and Cellular Endocrinology.

[46]  D. Stocco,et al.  SF-1 (Steroidogenic Factor-1) and C/EBPβ (CCAAT/Enhancer Binding Protein-β) Cooperate to Regulate the Murine StAR (Steroidogenic Acute Regulatory) Promoter , 1999 .

[47]  I. Huhtaniemi,et al.  Functional assessment of the calcium messenger system in cultured mouse Leydig tumor cells: regulation of human chorionic gonadotropin-induced expression of the steroidogenic acute regulatory protein. , 1999, Endocrinology.

[48]  I. Huhtaniemi,et al.  Molecular Mechanisms of Thyroid Hormone-stimulated Steroidogenesis in Mouse Leydig Tumor Cells , 1999, The Journal of Biological Chemistry.

[49]  M. K. Meintzer,et al.  Insulin-like Growth Factor I-mediated Activation of the Transcription Factor cAMP Response Element-binding Protein in PC12 Cells , 1999, The Journal of Biological Chemistry.

[50]  J. Veldhuis,et al.  Mechanisms of insulin-like growth factor I augmentation of follicle-stimulating hormone-induced porcine steroidogenic acute regulatory protein gene promoter activity in granulosa cells. , 1999, Endocrinology.

[51]  D. Stocco.  The steroidogenic acute regulatory (StAR) protein. , 1999, Medicina.

[52]  J. Veldhuis,et al.  Mechanisms of Insulin-Like Growth Factor I Augmentation of Follicle-Stimulating Hormone-Induced Porcine Steroidogenic Acute Regulatory Protein Gene Promoter Activity in Granulosa Cells* *This work was supported by the Lalor Foundation, NIH National Research Service Awards Grants HD-07382 and HD-0801 , 1999, Endocrinology.

[53]  I. Huhtaniemi,et al.  Regulation of luteinizing hormone receptor gene expression by insulin-like growth factor-I in an immortalized murine Leydig tumor cell line (BLT-1) , 1998, Biology of reproduction.

[54]  S. Azhar,et al.  Simultaneous induction of an HDL receptor protein (SR-BI) and the selective uptake of HDL-cholesteryl esters in a physiologically relevant steroidogenic cell model. , 1998, Journal of lipid research.

[55]  H. Watari,et al.  The Mechanism of Action of Steroidogenic Acute Regulatory Protein (StAR) , 1998, The Journal of Biological Chemistry.

[56]  R. Schwartz,et al.  GATA-4 and Nkx-2.5 Coactivate Nkx-2 DNA Binding Targets: Role for Regulating Early Cardiac Gene Expression , 1998, Molecular and Cellular Biology.

[57]  V. Rouiller-Fabre,et al.  Expression and Effect of Insulin-Like Growth Factor I on Rat Fetal Leydig Cell Function and Differentiation. , 1998, Endocrinology.

[58]  E. Lalli,et al.  DAX-1 blocks steroid production at multiple levels. , 1998, Endocrinology.

[59]  H. Watari,et al.  Phosphorylation of Steroidogenic Acute Regulatory Protein (StAR) Modulates Its Steroidogenic Activity* , 1997, The Journal of Biological Chemistry.

[60]  D. Stocco,et al.  Inhibition of transcription affects synthesis of steroidogenic acute regulatory protein and steroidogenesis in MA-10 mouse Leydig tumor cells. , 1997, Endocrinology.

[61]  W. Wetsel,et al.  Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[62]  M. Kiriakidou,et al.  Multiple steroidogenic factor 1 binding elements in the human steroidogenic acute regulatory protein gene 5'-flanking region are required for maximal promoter activity and cyclic AMP responsiveness. , 1997, Biochemistry.

[63]  M. Gaestel,et al.  CREB is activated by UVC through a p38/HOG‐1‐dependent protein kinase , 1997, The EMBO journal.

[64]  W. Miller,et al.  The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. , 1996, The New England journal of medicine.

[65]  J. Saez,et al.  Transcriptional regulation of the lutropin/human choriogonadotropin receptor and three enzymes of steroidogenesis by growth factors in cultured pig Leydig cells. , 1996, European journal of biochemistry.

[66]  J. Baker,et al.  Effects of an Igf1 gene null mutation on mouse reproduction. , 1996, Molecular endocrinology.

[67]  D. Stocco,et al.  Regulation of the acute production of steroids in steroidogenic cells. , 1996, Endocrine reviews.

[68]  D. Stocco,et al.  The steroidogenic acute regulatory protein is induced by angiotensin II and K+ in H295R adrenocortical cells , 1995, Molecular and Cellular Endocrinology.

[69]  S. Tsai,et al.  Stimulation of Human Insulin Receptor Gene Expression by Retinoblastoma Gene Product (*) , 1995, The Journal of Biological Chemistry.

[70]  T. Osborne,et al.  Domains of transcription factor Sp1 required for synergistic activation with sterol regulatory element binding protein 1 of low density lipoprotein receptor promoter. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[71]  D. Driscoll,et al.  Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[72]  C T Roberts,et al.  Molecular and cellular aspects of the insulin-like growth factor I receptor. , 1995, Endocrine reviews.

[73]  A. Rogol,et al.  Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. , 1995, Science.

[74]  D. Clemmons,et al.  Insulin-like growth factors and their binding proteins: biological actions. , 1995, Endocrine reviews.

[75]  Y. Hasegawa,et al.  Characterization of the insulin-like growth factors (IGF) axis in a cultured mouse Leydig cell line (TM-3). , 1995, Growth regulation.

[76]  S. King,et al.  The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). , 1994, The Journal of biological chemistry.

[77]  J. Saez.  Leydig cells: endocrine, paracrine, and autocrine regulation. , 1994, Endocrine reviews.

[78]  N. Colburn,et al.  A family of mitogen-activated protein kinase-related proteins interacts in vivo with activator protein-1 transcription factor. , 1994, The Journal of biological chemistry.

[79]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[80]  E. Alpizar,et al.  Effects of insulin, insulin-like growth factor I, and gonadotropins on bovine granulosa cell proliferation, progesterone production, estradiol production, and(or) insulin-like growth factor I production in vitro. , 1993, Journal of animal science.

[81]  C. Roberts,et al.  Insulin-like growth factors. , 1992, Biological signals.

[82]  J. Orly,et al.  Luteinizing hormone induction of the cholesterol side-chain cleavage enzyme in cultured immature rat Leydig cells: No role of insulin-like growth factor-I? , 1992, Molecular and Cellular Endocrinology.

[83]  E. Nieschlag,et al.  The role of growth hormone and insulin-like growth factor I in the regulation of male reproductive function. , 1992, Hormone research.

[84]  P. Chatelain,et al.  Regulation by growth factors og leydig cell differentiated functions , 1991, The Journal of Steroid Biochemistry and Molecular Biology.

[85]  W. Chang,et al.  Human chorionic gonadotropin up-regulates insulin-like growth factor-I receptor gene expression of Leydig cells. , 1991, Endocrinology.

[86]  D. Stocco,et al.  The 30-kDa mitochondrial proteins induced by hormone stimulation in MA-10 mouse Leydig tumor cells are processed from larger precursors. , 1991, The Journal of biological chemistry.

[87]  O. Pignataro,et al.  Studies with insulin and insulin-like growth factor-I show that the increased labeling of phosphatidylinositol-3,4-bisphosphate is not sufficient to elicit the diverse actions of epidermal growth factor on MA-10 Leydig tumor cells. , 1990, Molecular endocrinology.

[88]  R. Horikawa,et al.  Growth hormone and insulin-like growth factor I stimulate Leydig cell steroidogenesis. , 1989, European journal of pharmacology.

[89]  M. Serio,et al.  Insulin-like growth factor-I (IGF-I) and IGF-I receptor in human testis: an immunohistochemical study. , 1988, Fertility and sterility.

[90]  M. Dufau.  Endocrine regulation and communicating functions of the Leydig cell. , 1988, Annual review of physiology.

[91]  P. Chatelain,et al.  Differentiating effects of somatomedin-C/insulin-like growth factor I and insulin on Leydig and Sertoli cell functions. , 1988, Reproduction, nutrition, developpement.

[92]  I. Wool,et al.  The primary structure of rat ribosomal protein L19. A determination from the sequence of nucleotides in a cDNA and from the sequence of amino acids in the protein. , 1987, The Journal of biological chemistry.

[93]  E. Froesch,et al.  Insulin and Insulin-Like Growth Factor I , 1987 .

[94]  L. Pon,et al.  Acute ACTH regulation of adrenal corticosteroid biosynthesis. Rapid accumulation of a phosphoprotein. , 1986, The Journal of biological chemistry.

[95]  L. Terracio,et al.  Characterization of insulin and insulin-like growth factor I receptors of purified Leydig cells and their role in steroidogenesis in primary culture: a comparative study. , 1986, Endocrinology.

[96]  R. V. Rebois.  Establishment of gonadotropin-responsive murine leydig tumor cell line , 1982, The Journal of cell biology.

[97]  U. K. Laemmli,et al.  Cleavage of structural proteins during , 1970 .