Hunzicker-Dunn, Mary
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Research Interests
The focus of my lab is to elucidate the signaling pathways by which the prototypical glycoprotein hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH) signal to initiate cellular responses of differentiation and proliferation. Our studies are carried out in the native environment of the ovarian granulosa cell so that physiologically relevant data can be obtained. Both LH and FSH signal predominately via the second messenger cAMP and its target protein kinase A (PKA). We have shown that both FSH and LH signal via PKA to activate the MAPK/ERK pathway, although the mechanism by which PKA signals into this pathway differs for LH and FSH in immature versus mature granulosa cells. In immature granulosa cells, FSH regulates MAPK/ERK activation by regulating the association of an inhibitory protein tyrosine phosphatase with MAPK/ERK. However, regulation of this MAPK/ERK pathway by LH occurs at an unidentified site upstream of MAPK/ERK. Additional studies are needed to dissect the pathway by which LH signals to the MAPK/ERK cascade as well as to identify the functional significance of MAPK/ERK activation to granulosa cells. In an effort to elucidate how activation of PKA leads to distinct FSH- and LH- dependent responses, we have initiated studies on the A-kinase anchoring protein (AKAP) family of proteins and have identified unique regulation AKAPs in ovarian cells. AKAPs are very interesting proteins which not only dock PKA near its substrate but also appear to function as scaffolds for other signaling pathways, by binding a variety of signaling proteins including other protein kinases, phosphosphatases, and phosdiesterases. The functions of these AKAPs in ovarian granulosa cells and their requirement for signaling by both LH and FSH is currently under investigation.

Publications
Hunzicker-Dunn M and Birnbaumer L  (2002)  Cell-Free Membrane Desensitization Assay for G Protein-Coupled   Receptors.  Meth Enzymology  343, 394-404.

Duan WR, Ito M, Park Y, Maizels ET, Hunzicker-Dunn M, Jameson JL (2002)  Gonadotropin releasing hormone (GnRH) regulates early growth response protein 1 (ERG-1) transcription through multiple promoter elements.  Molecular Endo 16, 221-233,

Mukherjee S, Gurevich VV, Preninger A, Hamm H, Bader M-F, Fazleabas A, Birnbaumer L, and Hunzicker-Dunn M. (2002)   Aspartic Acid 564 in the Third Cytoplasmic Loop of Luteinizing Hormone/Choriogonadotropin Receptor is Crucial for   Phosphorylation-Independent Interaction with Arrestin2. J Biol Chem ,277, 17916-17927.

Salvador LM, Maizels ET, Hales, D.B., Miyamoto E, Yamamoto,H. and Hunzicker-Dunn M (2002) . Acute Signaling by the  Luteinizing Hormone (LH) Receptor is Independent of Protein Kinase C Activation. Endocrinology 143, 2986-2994.

Hunzicker-Dunn M, Gurevich VV, Casanova JE, and Mukherjee S (2002)  ARF6:  A Newly Appreciated Player in G Protein  Coupled Receptor Desensitization.  FEBS Lett, 521, 3-8.

Srisuparp S, Strakova Z, Brudney A, Mukherjee S, Reierstad S, Hunzicker-Dunn M, Faxleabas AT (2003) Signal transduction pathways activated by chorionic gonadotropin (CG) in the primate endometrial epithelial cells. Biol  Reprod 68, 457-464.

Hunzicker-Dunn M.  (2003)  Proteins and Cell Regulation.  Volume I. ARF Family GTPases “A role for ARF6 in G protein-coupled receptor desensitization”, Kluwer Academic Publishers, Boston, Richard A. Kahn,  ed, pp. 305-324  

Cottom J, Salvador L,  Maizels ET,  Reierstad S, Park Y, Carr D, Davare MA, Hell J,  Dent P, Palmer S, Kawakatsu H,  Ogata M, and Hunzicker-Dunn  M (2003)  Follicle Stimulating Hormone Stimulates Activation of Extracellular Regulated Kinases via Protein Kinase A-Dependent Phosphorylation of a 100 kDa Phosphotyrosine Phosphatase , J Biol Chem  278, 7167-7179.

Hunzicker-Dunn M, Barisas G, Song J, Roess DA (2003) Membrane Organization of Luteinizing Hormone Receptors   Differs between Actively Signaling and Desensitized Receptors. J Biol Chem 278, 42744-42749.

Soloff MS, Gal S, Hoare S, Peters CA, Hunzicker-Dunn M, Anderson GD, Wood TG (2003) Cloning,  characterization, and expression of the rat relaxin gene. Gene 323, 149-155.

Alam H, Maizels ET, Park Y, Ghaey S, Feiger ZJ, Chandel NS, Hunzicker-Dunn M. (2004) FSH activation of HIF-1 by the PI3-kinase/AKT/Rheb/mTOR pathway is necessary for induction of select protein markers of follicular differentiation.  J Biol Chem 279, 19421-19440.

Salvador LM, Flynn MP, Avila J, Reierstad S, Maizels ET, Park Y, Alam H, Scott JD, Carr DW, and Hunzicker-Dunn M.    (2004)  Neuronal  microtubule-associated protein 2D is a functional RI A-kinase anchoring protein in rat ovarian granulosa cells.   J Biol  Chem 279, 27621-27632.

Van der Zee EA, Palm IF, O’Connor M, Maizels ET, Hunzicker-Dunn M, Disterhoft JF.  (2004)  Aging-related alterations in the distribution of Ca2+-dependent PKC isoforms in rabbit hippocampus.  Hippocampus 14, 849-860.

Park Y, Maizels ET, Feiger Z, Alam H, Peters CA, Woodruff  T., Unterman T, Lee EJ, Jameson  JL, and Hunzicker-Dunn  M (2005)  Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-Dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad.  J Biol Chem 280, 9135-9148.

Hunzicker-Dunn M and Mayo K (2006)  Gonadotropin signaling in the ovary.  The Physiology of Reproduction, 3rd Edition, Jimmy D. Neil, editor, Elsevier, Inc., San Diego, CA, pp. 547-92.

Hunzicker-Dunn M, and Maizels ET.   FSH signaling pathways in immature granulosa cells that regulate target gene expression:  Branching out from protein kinase A.  Cellular  Signaling 18, 1351-59.

Parakh TN, Hernandez JA, Grammer JC, Weck J, Hunzicker-Dunn M, Zeleznik AJ, Nilson JH.  Follicle-stimulating hormone/AMP regulation of aromatase gene expression requires beta-catenin. Proc Natl Acad Sci. 103, 12435-12440.