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A Slominski

Publications and source records attributed to A Slominski.

98 records · Page 6Linked to original sources
PubMedDate not supplied

L-tyrosine, L-dopa, and tyrosinase as positive regulators of the subcellular apparatus of melanogenesis in Bomirski Ab amelanotic melanoma cells.

In cultured cells of the Bomirski Ab amelanotic hamster melanoma line, the substrates of tyrosinase, L-tyrosine, and L-DOPA induce the melanogenic pathway. In this report, we demonstrate that these substrates regulate the subcellular apparatus involved in their own metabolism and that this regulation is under the dynamic control of one of the components of this apparatus, tyrosinase, via tyrosine hydroxylase activity. Culturing cells with nontoxic but melanogenically inhibitory levels of phenylthiourea (PTU; 100 microM) strongly inhibits induction of both the tyrosine hydroxylase and DOPA oxidase activities of tyrosinase by L-tyrosine (200 microM) but has no effect on the induction of either activity by L-DOPA (50 microM). De novo synthesis of premelanosomes precedes the onset of tyrosine-induced melanogenesis. Thereafter, increases in the population of melanosomes (likewise inhibited by PTU) correlate positively with increases in tyrosinase activity induced by L-tyrosine. Melanogenesis induced by L-DOPA in the absence of L-tyrosine is rate-limited not by tyrosinase but by inadequate melanosome synthesis. Our findings indicate that in Bomirski Ab amelanotic hamster melanoma cells the synthesis of the subcellular apparatus of melanogenesis is initiated by L-tyrosine and is regulated further by tyrosinase and L-DOPA, which serves as a second messenger subsequent to tyrosine hydroxylase activity.

Animals↗
PubMedDate not supplied

Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs.

BACKGROUND: Observations that epidermal cells release both corticotropin-releasing hormone (CRH) and proopiome lanocortin (POMC) peptides has raised questions about the physiological relevance of this hypothalamo-pituitary-like system in mammalian skin. As CRH has shown anti-proliferative effects on cultured keratinocytes, we tested whether CRH can also regulate growth of melanoma cells. MATERIALS AND METHODS: CRH, [D-Glu20]-CRH, [D-Pro5]-CRH, acetyl-cyclo(30-33)[D-Phe12,D-Glu20,Nle21,D-His32,Lys33,D-Nle38]-CRH(4-41), acetyl-cyclo(30-33)[D-Phe12,Nle18,D-Glu20,Nle21,D-Ala32]-urotensin I(4-41), urocortin, and sauvagine were tested on Cloudman melanoma cell proliferation in culture and B16 melanoma tumor growth in C57B1/6 mice. Calcium-sensitive fluorescence measurements were used to examine the effect of CRH on intracellular Ca2+ signaling. The effects of CRH and [D-Glu20]-CRH on blood pressure were compared by measuring mean arterial pressure in anesthetized rats. RESULTS: CRH and six analogs were tested, and all demonstrated exceptional potency in inhibiting Cloudman cell proliferation in culture, with half-maximal effective concentrations ranging between 0.2 and 100 pM. The amplitude of ionomycin-induced Ca2+ influx into Cloudman cells grown in suspension was reduced by 50% after 48-hr exposure to CRH. Daily injections of CRH or [D-Glu20]-CRH, 100 micrograms/kg.day s.c., for 5 days, reduced net B16 tumor volume in mice by 30-60% compared to control animals. [D-Glu20]-CRH was less hypotensive compared to CRH, despite having similar anti-proliferative potency. CONCLUSION: CRH, and various analogs thereof, inhibit proliferation of Cloudman cells in culture, and inhibit B16 tumor growth rate in vivo, most likely by activation of endogenous CRH1 receptors and subsequent altered intracellular Ca2+ signaling. CRH analogs, such as [D-Glu20]-CRH, with less hypotensive activity may provide new directions of therapy for melanoma.

Amino Acid Substitution↗
PubMedDate not supplied

Dopa inhibits induced proliferative activity of murine and human lymphocytes.

L-DOPA, the product of enzymatic hydroxylation of L-tyrosine, is released by melanotic melanoma cells in vivo and in vitro. Here we report that DOPA at pharmacologically relevant micromolar doses dramatically inhibits the stimulation of DNA synthesis by lipopolysaccharide and concanavalin A in murine splenocytes and human lymphocytes, having little or no effect on unstimulated (control) lymphocytes or proliferating fibroblasts. Therefore we propose that melanogenically active melanoma cells can inhibit the host's immune response via the release of DOPA and/or its oxidation products.

Animals↗
PubMedDate not supplied

Molecular mechanisms governing melanogenesis in hamster melanomas: relative abundance of tyrosinase and catalase-B (gp 75).

Variants of the Bomirski family of hamster melanomas whose proliferative rates differ inversely with the genetically determined degree of melanogenesis were probed for two proteins critical in melanogenesis: tyrosinase and catalase-B (gp 75). The parental black tumor Ma contained both proteins in abundance. The amelanotic variant Ab, inducible in culture with L-tyrosine or L-dopa to form melanosomes and to melanize, had minimal tyrosinase, despite high levels of (tyr)mRNA, and no gp 75. Variant MI, hypomelanotic despite abundant tyrosinase, and synthesizing predominantingly pheo-(red) melanin, expressed barely detectable gp 75. These findings suggest a regulatory control of melanogenesis distal to (tyr)mRNA and strengthen the hypothesis that in vivo tyrosinase without catalase-B favors pheo- over eumelanogenesis.

Animals↗
PubMedDate not supplied

Is alopecia areata an autoimmune-response against melanogenesis-related proteins, exposed by abnormal MHC class I expression in the anagen hair bulb?

The etiology of alopecia areata (AA), a putative autoimmune disease characterized by sudden hair loss, has remained obscure. It is not understood, how the characteristic inflammatory infiltrate that selectively attacks anagen hair follicles in AA is generated. We hypothesize that this reflects an unexplored form of autoimmunity, a cytotoxic T cell attack on rhythmically synthesized autoantigens normally sequestered by a lack or very low level of MHC class I (MHC I)-expression, and suggest the following mechanism of AA pathogenesis: Microtrauma, neurogenic inflammation, or microbial antigens cause a localized breakdown of MHC I-"negativity" in the proximal anagen hair bulb via proinflammatory cytokines. This exposes autoantigens derived from melanogenesis-related proteins (MRP-DP), which are only generated during anagen, and triggers two successive waves of autoimmune responses: CD8+ cytotoxic T cells initiate AA after recognizing MRP-DP abnormally presented by MHC I molecules on hair matrix melanocytes and/or keratinocytes; a secondary attack, carried by CD4+ T cells and antigen presenting cells, is then mounted against MHC class II--presented additional autoantigens exposed by damaged melanocytes and keratinocytes. The latter causes most of the follicular damage, and extrafollicular disease, and depends greatly on the immunogenetic background of affected individuals. This unifying hypothesis explains the clinical heterogeneity and all salient features of AA, and argues that only the unlikely coincidence of multiple predisposing events triggers AA. The suppression of MHC I--expression and synthesis of MRP in the hair bulb, and the "tolerization" of MRP-DP autoreactive CD8+ T cells may be promising strategies for treating AA.

Alopecia Areata↗
PubMedDate not supplied

Transplantable melanomas in gerbils (Meriones unguiculatus). I. Origin, morphology and growth rate.

A family of serially transplanted melanomas in gerbils is described. These tumors were derived from the cutaneous melanotic melanoma that arose in 1 of 44 gerbils injected postnatally with N-ethyl-N-nitrosourea. It consists of a slow growing heavily melanotic parental line and two fast growing melanotic (FGM) and amelanotic (A-FGM) lines that appeared abruptly during serial transplantation of the parental tumor. The FGM melanotic line originated after a sudden acceleration of growth of the parental line during the 4th in vivo passage that was accompanied by a decrease in both pigmentation and metastasizing potential. The A-FGM derived from the depigmented tissue of the 7th in vivo passage of the FGM line and has been characterized by an amelanotic phenotype, an increased metastasizing potential and similar growth rate to that of the FGM. Once established, both lines expressed considerable phenotypic stability during serial transplantation in gerbils. Thus, the Zeman UJ melanomas represent the first established family of transplantable melanomas in gerbils, which serve as a model for pigmented cell and melanoma research and as a subject for a retrospective analysis of the phenomenon of tumor evolution.

Animals↗
PubMedDate not supplied

Inhibition of melanogenesis as an adjuvant strategy in the treatment of melanotic melanomas: selective review and hypothesis.

Melanogenesis generates immunosuppressive and mutagenic environment and alters cellular metabolism. Melanin can protect malignant melanocytes against chemo-, radio-, and photodynamic therapy. Therefore, we propose to inhibit melanogenesis as an adjuvant treatment modality during immuno-, radio-, chemo- and photodynamic therapy, and as a measure of reducing the probability of melanoma progression.

Antimetabolites, Antineoplastic↗