Insulin-like growth factor-I is an important antiapoptotic factor for rat leydig cells during postnatal development.
The present investigation examines the influence of IGF-I and the role of IGF-I receptor (IGF-IR) in the apoptosis/survival of Leydig cells. Immunohistochemical analysis of the rat testis at different ages revealed that the level of the phosphorylated IGF-IR increases from birth to d 20 of postnatal life, remaining high in the adult testis. Western blotting revealed that this level is higher in Leydig cells isolated from 40-d-old than from 10- or 60-d-old rats. Application of the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay revealed that IGF-I decreases the level of apoptosis in Leydig cells at all stages of development, and the selective inhibitor of IGF-IR, picropodophyllin, blocks this antiapoptotic effect. The mechanism underlying the antiapoptotic action of IGF-I involves the phosphatidylinositol 3-kinase/Akt pathway, and in immature Leydig cells, this growth factor enhances the expression of Bcl-2 and cellular inhibitor of apoptosis proteins 2, while preventing activation of caspase-3 by cleavage. Furthermore, IGF-II and high concentrations of insulin also evoke phosphorylation of IGF-IR and, like IGF-I, enhance the expression of the steroidogenic acute regulatory protein by Leydig cells. Inhibition of IGF-IR by picropodophyllin decreases the survival of Leydig cells, both in the presence and absence of IGF-I, demonstrating that signaling via the IGF-IR plays an important role in Leydig cell survival.
Colón
Eugenia
E
Department of Woman and Child Health, Paediatric Endocrinology Unit, Astrid Lindgren Children's Hospital, Karolinska Institute and University Hospital, SE 17176 Stockholm, Sweden. eugenia.colon@ki.se
Zaman
Farasat
F
Axelson
Magnus
M
Larsson
Olle
O
Carlsson-Skwirut
Christine
C
Svechnikov
Konstantin V
KV
Söder
Olle
O
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D007985:Leydig Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000254:growth & development* / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D004247:DNA; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin