The long term goal of collaborative research between the P.I. and the foreign collaborator is to determine the role of the high level expression of CYP51 (lanosterol 14alpha-demethylase cytochrome P450) in haploid, postmeiotic germ cells. This FIRCA proposal addresses a portion of this overall goal and will lead to an understanding of the biochemical mechanisms involved in cAMP-dependent transcription of CYP51 in somatic and germ cells.
The specific aims for the proposed three years are to study cAMP- dependent transcriptional regulation of CYP51 in steroidogenic (somatic) cells (Aim 1) and in haploid germ cells (Aim 2). The parent grant (DK28350) addresses ACTH (cAMP)-dependent transcription of genes (particularly encoding P450 enzymes) in the adrenal cortex, a process essential for maintenance of optimal steroidogenic capacity.
Aim 1 is an extension of DK28350 and will establish whether a link between cAMP-dependent transcription of genes encoding steroidogenic P450s (cholesterol metabolism) and CYP51 (cholesterol biosynthesis) exists in the adrenal cortex. It seems likely that two different signalling pathways, oxysterol/SRE and cAMP/CRE, interact to control CYP51 levels in steroidogenic cells. Preliminary data indicates that CYP51 is transcriptionally regulated by cAMP in haploid germ cells.
Aim 2 is a new direction for studies in DK28350 and will establish the biochemical basis of this postmeiotic transcriptional regulation. Results from these studies will provide a more detailed understanding of steroid hormone biosynthesis which is a major path of cholesterol metabolism and of spermatogenesis in male reproduction.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
1R03TW001174-01
Application #
2908312
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Katz, Flora N
Project Start
1999-09-30
Project End
2002-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Fink, Martina; Acimovic, Jure; Rezen, Tadeja et al. (2005) Cholesterogenic lanosterol 14alpha-demethylase (CYP51) is an immediate early response gene. Endocrinology 146:5321-31
Rozman, Damjana; Seliskar, Matej; Cotman, Marko et al. (2005) Pre-cholesterol precursors in gametogenesis. Mol Cell Endocrinol 234:47-56
Cotman, M; Jezek, D; Fon Tacer, K et al. (2004) A functional cytochrome P450 lanosterol 14 alpha-demethylase CYP51 enzyme in the acrosome: transport through the Golgi and synthesis of meiosis-activating sterols. Endocrinology 145:1419-26
Rezen, Tadeja; Debeljak, Natasa; Kordis, Dusan et al. (2004) New aspects on lanosterol 14alpha-demethylase and cytochrome P450 evolution: lanosterol/cycloartenol diversification and lateral transfer. J Mol Evol 59:51-8
Fon Tacer, Klementina; Kalanj-Bognar, Svjetlana; Waterman, Michael R et al. (2003) Lanosterol metabolism and sterol regulatory element binding protein (SREBP) expression in male germ cell maturation. J Steroid Biochem Mol Biol 85:429-38
Tacer, K Fon; Haugen, T B; Baltsen, M et al. (2002) Tissue-specific transcriptional regulation of the cholesterol biosynthetic pathway leads to accumulation of testis meiosis-activating sterol (T-MAS). J Lipid Res 43:82-9
Rozman, D; Cotman, M; Frangez, R (2002) Lanosterol 14alpha-demethylase and MAS sterols in mammalian gametogenesis. Mol Cell Endocrinol 187:179-87
Halder, Sunil K; Fink, Martina; Waterman, Michael R et al. (2002) A cAMP-responsive element binding site is essential for sterol regulation of the human lanosterol 14alpha-demethylase gene (CYP51). Mol Endocrinol 16:1853-63