Israel Hanukoglu, Ph. D.
Laboratory of Cell Biology
Faculty of Natural Sciences
Ariel University
Ariel 40700, Israel

Major Research Achievements of our Laboratory

The major achievements of our laboratory have been in the following areas:

  1. Mitochondrial cytochrome P450 systems involved in cholesterol conversion to pregnenolone and biosynthesis of other steroid hormones
    1.1. Gene and protein structure of P450 system enzymes
    1.2. Trophic hormone regulation of gene expression in adrenal cortex
    1.3. Regulation of the activity of P450 system enzymes
  2. Structures of NAD(P) dependent flavoproteins
  3. Molecular genetics of pseudohypoaldosteronism (PHA)
  4. Gene and protein structure of cytoskeletal proteins

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1. Characterization of the mitochondrial cytochrome P450 systems involved in steroid hormone biosynthesis

The mitochondrial multi-enzyme cytochrome P450 systems catalyze the first regulatory step in steroid hormone biosynthesis in all steroidogenic tissues (the conversion of cholesterol to pregnenolone), and C-11-hydroxylation of adrenal corticosteroids in the adrenal cortex only. These systems include three enzymes: adrenodoxin reductase, adrenodoxin, and a cytochrome P450 (P450scc - EC 1.14.15.6, or P450c11 - EC 1.14.15.4) which constitute an electron transport chain similar to the mitochondrial oxidative phosphorylation chain. During Ph. D. work I developed purification procedures for these enzymes and characterized their kinetic interactions to elucidate their membrane organization and behavior. Our current work continues in this field and concentrates on the structural and functional analysis of these enzymes and molecular biology of their regulation by trophic hormones.

Achievements:

1.1. Gene and protein structure of P450 system enzymes:

1.2. Trophic hormone regulation of gene expression in adrenal cortex:


1.3. Regulation of the activity of P450 system enzymes:

See publications list for relevant references


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2. Structures of NAD(P) dependent flavoproteins

Achievements:


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3. Molecular Genetics of Pseudohypoaldosteronism

Pseudohypoaldosteronism Type I (PHA) is a hereditary syndrome of salt wasting resulting from unresponsiveness to mineralocorticoid hormone aldosterone. Our work on this disease is a family project! My pediatrician brother first elucidated that PHA is manifested in two clinically and genetically distinct forms affecting either only the kidney or multiple target organs of aldosterone. Whereas the renal form of PHA is milder and is inherited as an autosomal dominant trait, the multi-system form carries a high rate of mortality and is inherited as an autosomal recessive trait. In most steroid hormone resistance syndromes a mutation in the steroid receptor was shown to be responsible for the disease. Thus, in our work we first examined the possible relationship between PHA and aldosterone receptor gene. Upon finding no relationship in the case of multi-system PHA we directed our attention to other candidate genes. The mutation was localized in the sodium channel subunit genes (see publications for the list of collaborators). Our current work concentrates on the identification of mutations in a series of affected families from Israel and from the UK.

Achievements:

See publications list for relevant references


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4. Analysis of gene and protein structure of cytoskeletal proteins

The cytoskeletal network of most mammalian cells includes three major types of filamentous systems: microfilaments, intermediate filaments and microtubules with respective diameters of 6 nm, 8-10 nm and 25 nm. Each of these filamentous systems is assembled from only one or two different subunits. The proteins that form these filaments are all encoded by multigene families the members of which are differentially expressed in different tissues. My post-doctoral work in this field concentrated on the analysis of cDNA and predicted protein sequence and structure of the cytoskeletal keratins which are members of the intermediate filament protein super-family.

Achievements:

See the publications list for the relevant references