July-August 2007 l Vol 13 l No 7-8

Think Zinc!
By Guest Editors Stefano L Sensi, Lorella MT Canzoniero and Susan Benoff
     
      In this special issue of Molecular Medicine we report on the 6^th Zinc Signals conference held last year at the Abbey of Monte Oliveto in Italy. At the meeting, more than 130 researchers from around the globe gathered to discuss the latest advances in the field of Zn²⁺ biology. Zinc is the second most abundant heavy metal in the human body, essential for proper development and function of brain, skin, reproductive, and digestive systems. Although eukaryotic cells contain as much as 200μM of this ion, the vast majority is tightly bound to intracellular proteins, serving in a functional and/or structural role or catalyzing the activity of more than 300 enzymes and proteins. Participants in the Zinc Signals meeting study the free ionic form (i.e., free or chelatable) Zn²⁺, whose concentration is considered to be in the picomolar range. This “free-Zn²⁺ constitutes a highly dynamic pool that mediates cell signaling.
      While, until recently, Zn²⁺-focused research has been hampered by the lack of adequate tools, technology is catching up and through the availability of transgenic models, Zn²⁺
specific fluorescent probes, and selective chelators we are now starting to fully reveal the role played by Zn2+ signaling in many physiological and patho-physiological conditions.
A key concept emerging today is that biological systems possess a finely tuned “Zn²⁺ set-point.” Prenatal zinc deficiency impairs brain development and results in serious cognitive deficits later in life. In the reproductive system, Zn²⁺ has been shown to be essential for testicular development as well as sperm motility. In the colon, the integrity of the epithelial layer is dependent upon zinc, and supplementation is highly effective in prevention of potentially deadly diarrhea. In the pancreatic islets, zinc is required for storage of insulin with which it is co-released, and it has been shown to affect hormone secretion. Zn2+ deficiency is also linked to taste disorders, skin lesions and wound healing. While Zn²⁺ deficiency can greatly impair function in many biological systems, excessive [Zn²⁺]i can also be deleterious. For instance, Zn²⁺ has been implicated in b-amyloid plaque formation in Alzheimer’s disease.
      At the cellular level, the “Zn²⁺ set point” is maintained by the concerted activity of Zn²⁺ many homeostatic systems.Alteration in the Zn²⁺ set point can have important consequences. Changes in the Zn²⁺ concentration, within a “physiological range,” have emerged as an important means to modulate signaling. In the central nervous system, for instance, such changes have been shown to regulate the activity of major receptors (GABA, NMDA, and glycine), ion channels, and transporters. Exciting new findings also have started to shed some light on the role played by synaptic Zn²⁺ in modulating long-term potentiation.
      Acute Zn²⁺ depletion, induced, for example, by cation-specific chelation, can be a potent trigger for apoptosis via inhibition of the caspase system, effects on Zn²⁺ binding transcription factors, and direct modulation of the ionic exchange between the cytoplasm, the perinuclear compartment, and the nucleoplasm. Intracellular Zn²⁺ accumulation, on the other hand, mediates toxic effects in a variety of pathological conditions, including cerebral ischemia, brain trauma and epilepsy in addition to b-cell death during diabetes. Changes in expression of Zn²⁺ homeostatic proteins, for example, ZIP1 and LIV1, can also be catastrophic, and have been linked to prostate and breast cancer.
Intriguingly, recent evidence demonstrates Zn²⁺ crosstalk with the other cell signaling molecules, especially the signaling cation “par excellence,” Ca²⁺. Given that the molar potency of Zn²⁺ in activating/modulating cell signaling pathways is in many cases much higher than Ca²⁺, it is not far-fetched to envision that Zn²⁺ will soon compete with Ca²⁺ for the role of major signaling modulator in cell biology.
      The 2006 Zinc Signals conference superbly illustrated the extraordinary variety of aspects related to Zn²⁺ biology: imaging tools, cell physiology, system physiology, and patho-physiology. Each of these topics is covered in this special issue and represents the cutting edge and new frontiers in a highly dynamic and visible field of biology.
      After the outstanding 2006 Zinc Signals meeting, it was clear that the richness of Zn²⁺-focused research justifies the establishment of an international organization devoted to its study. In January of this year, therefore, we established the Society for Zinc Biology (SZB, www.sfzb.org), and are proud of the overwhelmingly enthusiastic response. By this means, we have successfully assembled the most prominent Zn2+ biologists and are now looking forward to the 1st SZB meeting to be held in February 2008 in Banff, Canada.
Stay tuned for the zinc revolution…

The Zinc Sensing Receptor, a Link Between Zinc and Cell Signaling
Michal Hershfinkel, William F Silverman, and Israel Sekler
Page 331 l View article: PDF (932 KB) HTML

Mechanism and Regulation of Cellular Zinc Transport
Israel Sekler, Stefano L Sensi, Michal Hershfinkel, and William F Silverman
Page 337 l View article: PDF (192 KB) HTML

Zinc Inhibits Astrocyte Glutamate Uptake by Activation of Poly(ADP-ribose) Polymerase-1
Sang Won Suh, Koji Aoyama, Conrad C Alano, Christopher M Anderson, Aaron M Hamby, and Raymond A Swanson
Page 344 l View article: PDF (320 KB) HTML

Intracellular Zinc Release, 12-Lipoxygenase Activation and MAPK Dependent Neuronal and Oligodendroglial Death
Yumin Zhang, Elias Aizenman, Donald B DeFranco, and Paul A Rosenberg
Page 350 l View article: PDF (652 KB) HTML

Mild Acidosis Enhances AMPA Receptor-Mediated Intracellular Zinc Mobilization in Cortical Neurons
Valerio Frazzini, Ilario G Rapposelli, Carlo Corona, Erica Rockabrand, Lorella MT Canzoniero, and Stefano L Sensi
Page 356 l View article: PDF (192 KB) HTML

Differential Gene Expression After Zinc Supplementation and Deprivation in Human Leukocyte Subsets
Hajo Haase, Dawn J Mazzatti, Andrew White, Klaus H Ibs,Gabriela Engelhardt, Silke Hebel, Jonathan R Powell, and Lothar Rink
Page 362 l View article: PDF (1.4 MB) HTML
Supplemental Data 1 PDF (11.8 MB)
Supplemental Data 2 PDF (11.8 MB)
Supplemental Data 3 PDF (11.6 MB)

Cellular Zinc and Redox Buffering Capacity of Metallothionein/ Thionein in Health and Disease
Wolfgang Maret and Artur Krezel
Page 371 l View article: PDF (82 KB) HTML

Müller Cell Zinc Transporter-3 Labeling Suggests a Role in Outer Retina Zinc Homeostasis
Stephen Redenti and Richard L Chappell
Page 376 l View article: PDF (412 KB) HTML

The Role of Zinc in Cerebral Ischemia
Sherry L Galasso and Richard H Dyck
Page 380 l View article: PDF (345 KB) HTML

The +838 C/G MT2A Polymorphism, Metals and Inflammatory/Immune Response in Carotid Artery Stenosis in Elderly People
Robertina Giacconi, Elisa Muti, Marco Malavolta, Catia Cipriano, Laura Costarelli, Gianni Bernardini, Nazzarena Gasparini, Erminia Mariani, Vittorio Saba, Gianfranco Boccoli, and Eugenio Mocchegiani
Page 388 l View article: PDF (132 KB) HTML

The Emerging Role of the LIV-1 Subfamily of Zinc Transporters in Breast Cancer
Kathryn M Taylor, Helen E Morgan, Kathryn Smart, Normawati M Zahari, Sara Pumford, Ian O Ellis, John FR Robertson, and Robert I Nicholson
Page 396 l View article: PDF (724 KB) HTML

Zinc in Human Health: Effect of Zinc on Immune Cells (Vol14/No 5-6)
Ananda S Prasad
Page 353 l View article: PDF (72 KB) HTML

Analysis of TBX1  Variation in Patients with Psychotic and Affective Disorders
Birgit H Funke, Todd Lencz, Christine T Finn, Pamela DeRosse, G David Poznik, Alex M Plocik, John Kane, John Rogus, Anil K Malhotra, and Raju Kucherlapati
A significant portion of patients with 22q11 deletion syndrome (22q11DS) develop psychiatric disorders including schizophrenia and and other psychotic and affective symptoms. The gene/s responsible for this syndrome may also play a significant role in the etiology of nonsyndromic psychiatric disease. The primary candidate 22q11DS gene, TBX1, is involved in epithelial and mesenchymal interactions, a mechanism which is crucial for the development of a wide variety of organs including the forebrain, heart, face and limbs. TBX1 may therefore play a role in brain development and thus in 22q11DS-associated as well as nonsyndromic psychiatric disease. Funke et al. (407-414) tested whether variation in the TBX1 gene could be associated with psychotic and affective disorders relevant to 22q11DS in Caucasian patients. Results show that allele and haplotype frequencies were not significantly different between affected cases and controls.  Therefore, it is unlikely that the TBX1 gene plays a major role in the genetic etiology of nonsyndromic schizophrenia and other psychiatric disorders observed in 22q11DS. However, 22q11DS may still represent a genetic subclass of schizophrenia which is very similar but genetically distinct from the nonsyndromic form. In this case TBX1 may still contribute to the risk of developing psychiatric disease in patients with 22q11DS.
Page 407 l View article: PDF (728 KB) HTML

Nicotinamide N-Methyltransferase Upregulation Inversely Correlates with Lymph Node Metastasis in Oral Squamous Cell Carcinoma
Davide Sartini, Andrea Santarelli, Valentina Rossi, Gaia Goteri, Corrado Rubini, Domenico Ciavarella, Lorenzo Lo Muzio, and Monica Emanuelli
Squamous cell carcinoma is the most common type of cancer in the oral cavity, representing 90% of all oral cancers.  Treatment methods for oral squamous cell carcinoma (OSCC) usually include surgery or radiation treatment, with or without chemotherapy.  Despite advances in surgical techniques and therapies, the mortality rate of OSCC has shown little improvement over the last three decades.  The overall five-year survival rate of these patients is less than 50% and diagnostic delay seems to be responsible for this poor prognosis.  Abnormal expression of nicotinamide N-methyltransferase (NNMT), an enzyme involved in the biotransformation and detoxification of many xenobiotics, has been reported in various cancers.  Upregulation of NNMT is inversely related to tumor size, suggesting the enzyme may play a role in an initial step of malignant conversion.  Studying tumor and non-tumor tissues, Sartini et al. (415-421) found a correlation between NNMT enzyme gene upregulation and favorable prognosis in OSCC patients.  While the function of NNMT in cancer cell metabolism is still unclear, these data suggest that NNMT may serve as a therapeutic target and potential biomarker for oral squamous cell carcinoma, which may lead to earlier detection of this disease.
Page 415 l View article: PDF (356 KB) HTML

Apert p.Ser252Trp Mutation in FGFR2 Alters Osteogenic Potential and Gene Expression of Cranial Periosteal Cells
Roberto D Fanganiello, Andréa L Sertié, Eduardo M Reis, Erika Yeh, Nélio AJ Oliveira, Daniela F Bueno, Irina Kerkis, Nivaldo Alonso, Sérgio Cavalheiro, Hamilton Matsushita, Renato Freitas, Sergio Verjovski-Almeida, and Maria Rita Passos-Bueno
Craniosynostosis is a common malformation in which the sutures form prematurely. Early corrective surgery is necessary to allow proper brain and skull growth. As a result of continuous bone healing defects, several surgeries are usually necessary during childhood and puberty. Apert syndrome (AS) is a severe form of craniosynostosis caused by mutations in the fibroblast growth factor 2 receptor (FGFR2). The periosteum, a dense fibrous membrane covering bone surfaces may play a role in cranial bone regeneration but the contribution of the periosteum to AS and its cranial pathophysiology is unknown. Here, Fanganiello, Sertié et al. (422-442) observed that AS periosteal cells (harboring the FGFR2 p.Ser252Trp mutation) are more committed towards the osteblast lineage. Additionally, a global gene expression analysis on AS patients periosteal cells showed that several genes involved in cellular proliferation and extracellular matrix formation are differentially expressed when compared with control subjects. While additional studies are needed these results suggest that the periosteum may be involved in the pathophysiology of craniosynostosis.
Page 422 l View article: PDF (1.3 MB) HTML

Potential of Diallyl Sulfide Bearing pH-Sensitive Liposomes in Chemoprevention of DMBA-Induced Skin Papilloma
Arif Khan, Yogeshwer Shukla, Neetu Kalra, Maroof Alam, Manzoor Gatoo Ahmad, Seema Rashid Hakim, and Mohammad Owais
Throughout history garlic has been shown to possess potential health benefits.  The chemotherapeutic and antitumor activity associated with garlic has been attributed to the presence of various organosulfide based compounds including diallyl sulfide (DAS). This active component of garlic possesses strong anti-neoplastic properties against various forms of cancer.  Topical application is the most promising approach for local treatment of skin tumors.  More efficient delivery methods are necessary to ensure that drugs are effectively carried to their targets because topical delivery of small molecules tend to diffuse across the skin surface.  Topical liposome-based formulations have shown promise in this area and in the present study Arif et al. (443-451) evaluated the effects of liposomised-DAS against dimethyl benz (a) anthracene (DMBA)-induced skin papilloma. Results showed that liposomised-DAS could effectively delay the onset of tumorogenesis and reduce the cumulative numbers and size of tumor papillomas in treated mice. The promising chemo-preventive nature of liposomal DAS may form the basis for establishing effective means of controlling various forms of cancer including skin papilloma.
Page 443 l View article: PDF (276 KB) HTML