The pink‐eyed dilution protein (p) plays a pivotal role in the synthesis of eumelanin. In its absence, critical melanosomal proteins fail to traffic to the melanosome. Pink‐eyed dilution gene ( P ) mutations are the most common cause of tyrosinase‐positive oculocutaneous albinism worldwide. Thus, reports that bafilomycin A1 was able to induce synthesis of melanin in tyrosinase‐positive melanomas led us to test the drug on p‐null murine melanocytes. We found that in melanocytes lacking p, bafilomycin A1 was able to induce melanin synthesis. These cells, once transfected with an expression vector encoding an epitope‐tagged p transcript, failed to respond to the drug. The increase in melanin synthesis is accompanied by a reduction in tyrosinase protein cleavage and secretion with subsequent accumulation within the melanocyte. Bafilomycin A1 has also been reported to induce pigmentation of normal Caucasian melanocytes. Based on these data we hypothesize that p may serve as a key control point at which ethnic skin color variation is determined.
In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology.
<div>Abstract<p><b>Purpose:</b> In certain cancers, <i>MDM2</i> SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among <i>MDM2</i> SNP309, age at diagnosis, and gender among melanoma patients.</p><p><b>Experimental Design:</b> Prospectively enrolled melanoma patients (<i>N</i> = 227) were evaluated for <i>MDM2</i> SNP309 and the related polymorphism, p53 Arg72Pro. DNA was isolated from patient blood samples, and genotypes were analyzed by PCR-restriction fragment length polymorphism. Associations among <i>MDM2</i> SNP309, p53 Arg72Pro, age at diagnosis, and clinicopathologic features of melanoma were analyzed.</p><p><b>Results:</b> The median age at diagnosis was 13 years earlier among women with a SNP309 GG genotype (46 years) compared with women with TG+TT genotypes (59 years; <i>P</i> = 0.19). Analyses using age dichotomized at each decade indicated that women with a GG genotype had significantly higher risks of being diagnosed with melanoma at ages <50 years compared with women ≥50 years, but not when the comparison was made between women <60 and ≥60 years. At ages <50 years, women with a GG genotype had a 3.89 times greater chance of being diagnosed compared with women with TG+TT genotypes (<i>P</i> = 0.01). Similar observations were not seen among men.</p><p><b>Conclusions:</b> Our data suggest that <i>MDM2</i> may play an important role in the development of melanoma in women. The <i>MDM2</i> SNP309 genotype may help identify women at risk of developing melanoma at a young age.</p></div>
To determine the prevalence of epilepsy and its associated disabilities in rural South African children aged 2-9 years.Eight villages in the district of Bushbuckridge, Northern Province, South Africa.A two-phase design was used. The first phase involved screening children on a house-to-house basis by interviewing mothers or caregivers using an internationally validated questionnaire for detecting childhood disability in developing countries. The second phase consisted of a paediatric/neurodevelopmental assessment of the children who screened positive.A total of 6,692 children were screened; 722 (10.8%) had a paediatric evaluation and 49 (0.73%) had epilepsy. The lifetime and active prevalences of epilepsy in these children were 7.3/1,000 and 6.7/1,000 respectively. Associated developmental disability was recorded in 35 affected children (71.4%), including 8 (16.3%) in whom this was moderate to severe. More than a half of the children with epilepsy (57.1%) did not receive anticonvulsant medication.The prevalence of epilepsy in the rural childhood population investigated is higher than that recorded in most similar studies from sub-Saharan Africa, and the poor utilisation of appropriate anticonvulsant treatment is cause for concern. This study highlights the paucity of relevant information on the epidemiology of epilepsy in South Africa and that the system available for its management, especially in rural areas, appears to have functional deficiencies. Appropriate research is needed to identify the problems in service delivery and to enable the planning and implementation of an appropriate primary health care-based system for the diagnosis and management of epilepsy in children.
Vitiligo is an acquired depigmentary disorder of the skin that results from the selective destruction of melanocytes, generally during the second decade of life and affecting approximately 1% of the population worldwide. Loss of cutaneous pigment appears to render the skin susceptible to premature aging and cancer. In addition this disease can be socially devastating for afflicted individuals. The etiology of vitiligo is poorly understood. The present dogma suggests that genetic factors render the melanocyte fragile thus predisposing individuals to developing vitiligo. When subjected to instigating factors, these susceptible, fragile melanocytes undergo apoptosis. Autoimmune factors then perpetuate the removal of the melanocyte component from the skin. In the majority of cases the instigating factors are not known (idiopathic vitiligo), however a small sub‐set of individuals develop contact/occupational vitiligo following exposure to particular chemicals. Many of these chemicals have been implicated in both contact/occupational vitiligo and chemical leukoderma. Both conditions present with well‐defined, depigmented skin lesions that develop following exposure. Only in the case of vitiligo does the depigmentation spread beyond the areas of contact, probably via an immune‐mediated mechanism. The largest class of chemicals known to trigger contact/occupational vitiligo is the phenolic/catecholic derivatives. Many have been demonstrated to be preferentially cytotoxic to melanocytes, with high‐dose exposure resulting in the initiation of apoptosis. Phenolic/catecholic derivatives are structurally similar to the melanin precursor tyrosine, and therefore tyrosinase was originally implicated as a mediator of cytotoxicity. However, our data suggests that tyrosinase‐related protein‐1, rather than tyrosinase, facilitates toxicity, possibly by catalytic conversion of the compounds, which results in the generation of radical oxygen species. The ensuing oxidative stress then triggers activation of cellular free radical scavenging pathways to prevent cell death. Genetic inability of melanocytes to tolerate and/or respond to the oxidative stress may underlie the etiology of contact/occupational vitiligo.
In certain cancers, MDM2 SNP309 has been associated with early tumor onset in women. In melanoma, incidence rates are higher in women than in men among individuals less than 40 years of age, but among those older than 50 years of age, melanoma is more frequent in men than in women. To investigate this difference, we examined the association among MDM2 SNP309, age at diagnosis, and gender among melanoma patients.
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