The Follicle Stimulating
Hormone (FSH) is an anterior
pituitary gonadotropin belonging
to the family of glycoprotein
hormones that includes thyroid
stimulating hormone (TSH),
Leutinizing Hormone (LH)
and Chorionic Gonadotropin
(1,2). FSH controls the growth
and maturation of follicles
in the females and spermatogenesis
in males. FSH is a heterodimer
and shares a common alpha
sub-unit with the other glycoprotein
hormones in its family (3)
and has a specific beta subunit
that confers receptor specificity
and biological activity to
the hormone (4). FSH acts
through the FSH receptor
(FSHR), a G protein coupled
receptor (GPCR) that is expressed
exclusively on the granulosa
cells of ovaries and Sertoli
cells of the testis (5) in
humans. FSH signaling involves
activation of adenylyl cyclase
activity and the increased
production of cAMP. This
activates the cAMP dependent
protein kinases such as PKA
(6), PKB (Akt) and PKC (7)
that, in turn, lead to the
phosphorylation of specific
transcription factors such
as cAMP response element
binding protein (CREB) (8,9)
and Forkhead box protein
O1 (FOXO1)10. In addition
to activation of PI3K/Akt
module, PKA also induces
p38 mapk which, in turn,
controls other kinase cascades
(11). Activated Akt also
induces the mTOR axis that
stimulates mRNA translation
by phosphorylating p70 S6
kinase and, consequently,
the 40 S ribosomal protein
S6.that results in the activation
of eukaryotic initiation
factor (eIF) 4E (12). It
also indirectly aids in the
activation of extracellular
signal-regulated protein
kinases (ERKs) (13). FSH
induces important genes required
for steroidogenesis as well
as growth and maturation
of germ cells. The important
target genes include aromatase
(CYP19A1) (14), the lutenizing
hormone receptor (LHR) and
the vascular endothelial
growth factor (VEGF) (15).
1. Pierce JG & Parsons
TF. (1981) Glycoprotein hormones:
structure and function. Annu
Rev Biochem. 50, 465-95.
2. Stockell Hartree A & Renwick
AG. (1992) Molecular structures
of glycoprotein hormones
and functions of their carbohydrate
components. Biochem J. 287
( Pt 3), 665-79.
3. Fiddes JC & Goodman
HM. (1981) The gene encoding
the common alpha subunit
of the four human glycoprotein
hormones. J Mol Appl Genet.
1, 3-18.
4. Lindau-Shepard B, Roth
KE & Dias JA. (1994)
Identification of amino acids
in the C-terminal region
of human follicle-stimulating
hormone (FSH) beta-subunit
involved in binding to human
FSH receptor. Endocrinology.
135, 1235-40.
5. Simoni M, Gromoll J & Nieschlag
E. (1997) The follicle-stimulating
hormone receptor: biochemistry,
molecular biology, physiology,
and pathophysiology. Endocr
Rev. 18, 739-73.
6. DeManno DA, Cottom JE,
Kline MP, Peters CA, Maizels
ET & Hunzicker-Dunn M.
(1999) Follicle-stimulating
hormone promotes histone
H3 phosphorylation on serine-10.
Mol Endocrinol. 13, 91-105.
7. Su YQ, Xia GL, Byskov
AG, Fu GD & Yang CR.
(1999) Protein kinase C and
intracellular calcium are
involved in follicle-stimulating
hormone-mediated meiotic
resumption of cumulus cell-enclosed
porcine oocytes in hypoxanthine-supplemented
medium. Mol Reprod Dev. 53,
51-8.
8. Hagiwara M, Brindle P,
Harootunian A, Armstrong
R, Rivier J, Vale W, Tsien
R & Montminy MR. (1993)
Coupling of hormonal stimulation
and transcription via the
cyclic AMP-responsive factor
CREB is rate limited by nuclear
entry of protein kinase A.
Mol Cell Biol. 13, 4852-9.
9. Mukherjee A, Park-Sarge
OK & Mayo KE. (1996)
Gonadotropins induce rapid
phosphorylation of the 3',5'-cyclic
adenosine monophosphate response
element binding protein in
ovarian granulosa cells.
Endocrinology. 137, 3234-45.
10. Richards JS, Sharma SC,
Falender AE & Lo YH.
(2002) Expression of FKHR,
FKHRL1, and AFX genes in
the rodent ovary: evidence
for regulation by IGF-I,
estrogen, and the gonadotropins.
Mol Endocrinol. 16, 580-99.
11. Gonzalez-Robayna IJ,
Falender AE, Ochsner S, Firestone
GL & Richards JS. (2000)
Follicle-Stimulating hormone
(FSH) stimulates phosphorylation
and activation of protein
kinase B (PKB/Akt) and serum
and glucocorticoid-lnduced
kinase (Sgk): evidence for
A kinase-independent signaling
by FSH in granulosa cells.
Mol Endocrinol. 14, 1283-300.
12. Alam H, Maizels ET, Park
Y, Ghaey S, Feiger ZJ, Chandel
NS & Hunzicker-Dunn M.
(2004) Follicle-stimulating
hormone activation of hypoxia-inducible
factor-1 by the phosphatidylinositol
3-kinase/AKT/Ras homolog
enriched in brain (Rheb)/mammalian
target of rapamycin (mTOR)
pathway is necessary for
induction of select protein
markers of follicular differentiation.
J Biol Chem. 279, 19431-40.
13. Cottom J, Salvador LM,
Maizels ET, Reierstad S,
Park Y, Carr DW, Davare MA,
Hell JW, Palmer SS, Dent
P, Kawakatsu H, Ogata M & Hunzicker-Dunn
M. (2003) Follicle-stimulating
hormone activates extracellular
signal-regulated kinase but
not extracellular signal-regulated
kinase kinase through a 100-kDa
phosphotyrosine phosphatase.
J Biol Chem. 278, 7167-79.
14. Lindeberg M, Carlstrom
K, Ritvos O & Hovatta
O. (2007) Gonadotrophin stimulation
of non-luteinized granulosa
cells increases steroid production
and the expression of enzymes
involved in estrogen and
progesterone synthesis. Hum
Reprod. 22, 401-6.
15. Huang Y, Hua K, Zhou
X, Jin H, Chen X, Lu X, Yu
Y, Zha X & Feng Y. (2008)
Activation of the PI3K/AKT
pathway mediates FSH-stimulated
VEGF expression in ovarian
serous cystadenocarcinoma.
Cell Res. 18, 780-91.
|