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Department of Cell Biology (I.J.G.R., T.A., J.S.R.) Baylor
College of Medicine Houston, Texas 77030
Department of
Molecular and Cell Biology (P.B., G.L.F.) University of California
at Berkeley Berkeley, California 94720
The responsiveness of granulosa cells to FSH
(cAMP) changes as these cells switch from the proliferative stage in
growing follicles to the terminally differentiated, nonproliferating
stage after LH-induced luteinization. To analyze this transition, two
well characterized culture systems were used. 1) Granulosa cells
isolated from immature rats were cultured in serum-free medium, a
system that permits analysis of dynamic, short-term responses to
hormones/cAMP. 2) Granulosa cells from preovulatory (PO) follicles that
have been exposed in vivo to surge concentrations of hCG
(PO/hCG) were cultured in medium containing 1% FBS, a system that
permits analyses of cells that have undergo irreversible, long-term
changes associated with luteinization. To analyze the biochemical basis
for the switch in cAMP responsiveness, the localization of A-kinase
pathway components was related to the expression of two cAMP target
genes, aromatase (CYP19) and serum-and glucocorticoid-induced kinase
(Sgk). Components of the A-kinase pathway were analyzed by
Western blotting and indirect immunofluorescence using specific
antibodies to the C subunit, RII
/ß subunits, CREB (cAMP-regulatory
element binding protein), phospho-CREB, CBP (CREB binding protein), and
Sgk. Cellular levels of C subunit and CREB were similar in all cell
types and hormone treatments. CREB and CBP were nuclear; RII/ß was
restricted to a cytoplasmic basket-like structure. Addition of FSH to
immature granulosa cells caused rapid nuclear import of C subunit
within 1 h. Nuclear C subunit decreased by 6 h after FSH but
could be rapidly reimported to the nucleus by the addition of forskolin
at 6, 24, or 48 h. Nuclear C subunit was associated with the rapid
but transient increases in phospho-CREB. FSH induced Sgk in a biphasic
manner in which the protein was nuclear at 1 h and cytoplasmic at
48 h. Aromatase mRNA was only expressed at 24–48 h after FSH, a
pattern that was not altered by phosphodiesterases or phosphatases. In
the luteinized (PO/hCG) granulosa cells, immunoreactive C subunit was
localized in a punctate pattern in the nucleus as well as to a
cytoplasmic basket-like structure, a distribution pattern not altered
by forskolin. Aromatase, Sgk, and phospho-CREB were expressed at
elevated levels in a non-forskolin-responsive manner. Most notable,
both phospho-CREB and Sgk were preferentially localized in a punctate
pattern within the cytoplasm and not altered by forskolin.
Collectively, these data indicate that when granulosa cells
differentiate to luteal cells the subcellular localization (nuclear
vs. cytoplasmic) of A-kinase pathway components changes
markedly. Thus, either the mechanisms of nuclear import and export or
the presence of distinct docking sites (and functions ?) dictate where
A-kinase, phospho-CREB and Sgk are localized in granulosa cells
compared with the terminally differentiated luteal cells.
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E. T. Maizels, A. Mukherjee, G. Sithanandam, C. A. Peters, J. Cottom, K. E. Mayo, and M. Hunzicker-Dunn Developmental Regulation of Mitogen-Activated Protein Kinase-Activated Kinases-2 and -3 (MAPKAPK-2/-3) in Vivo during Corpus Luteum Formation in the Rat Mol. Endocrinol., May 1, 2001; 15(5): 716 - 733. [Abstract] [Full Text]
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J. S. Richards New Signaling Pathways for Hormones and Cyclic Adenosine 3',5'-Monophosphate Action in Endocrine Cells Mol. Endocrinol., February 1, 2001; 15(2): 209 - 218. [Abstract] [Full Text]
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 J. S. Richards Graafian Follicle Function and Luteinization in Nonprimates Reproductive Sciences, January 1, 2001; 8(1_suppl): S21 - S23. [Abstract] [PDF]
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J. Y. Wu, I. J. Gonzalez-Robayna, J. S. Richards, and A. R. Means Female Fertility Is Reduced in Mice Lacking Ca2+/Calmodulin-Dependent Protein Kinase IV Endocrinology, December 1, 2000; 141(12): 4777 - 4783. [Abstract] [Full Text] [PDF]
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I. J. Gonzalez-Robayna, A. E. Falender, S. Ochsner, G. L. Firestone, and J. S. Richards Follicle-Stimulating Hormone (FSH) Stimulates Phosphorylation and Activation of Protein Kinase B (PKB/Akt) and Serum and Glucocorticoid-Induced Kinase (Sgk): Evidence for A Kinase-Independent Signaling by FSH in Granulosa Cells Mol. Endocrinol., August 1, 2000; 14(8): 1283 - 1300. [Abstract] [Full Text]
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B. D. Murphy Models of Luteinization Biol Reprod, July 1, 2000; 63(1): 2 - 11. [Abstract] [Full Text]
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T. N. Alliston, I. J. Gonzalez-Robayna, P. Buse, G. L. Firestone, and J. S. Richards Expression and Localization of Serum/Glucocorticoid-Induced Kinase in the Rat Ovary: Relation to Follicular Growth and Differentiation Endocrinology, January 1, 2000; 141(1): 385 - 395. [Abstract] [Full Text] [PDF]
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S. C. Sharma and J. S. Richards Regulation of AP1 (Jun/Fos) Factor Expression and Activation in Ovarian Granulosa Cells. RELATION OF JunD AND Fra2 TO TERMINAL DIFFERENTIATION J. Biol. Chem., October 20, 2000; 275(43): 33718 - 33728. [Abstract] [Full Text] [PDF]
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N. Perrotti, R. A. He, S. A. Phillips, C. R. Haft, and S. I. Taylor Activation of Serum- and Glucocorticoid-induced Protein Kinase (Sgk) by Cyclic AMP and Insulin J. Biol. Chem., March 16, 2001; 276(12): 9406 - 9412. [Abstract] [Full Text] [PDF]
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