210 research outputs found
MC1R functions, expression and implications for targeted therapy
No full textThe G protein-coupled MC1R is expressed in melanocytes and has a pivotal role in human skin pigmentation, with reduced function in human genetic variants exhibiting a red hair phenotype and increased melanoma predisposition. Beyond its role in pigmentation, MC1R is increasingly recognized as promoting UV-induced DNA damage repair. Consequently, there is mounting interest in targeting MC1R for therapeutic benefit. However, whether MC1R expression is restricted to melanocytes or is more widely expressed remains a matter of debate. In this paper, we review MC1R function and highlight that unbiased analysis suggests that its expression is restricted to melanocytes, granulocytes, and the brain
Smiliorachis nubilis Goding 1930, comb. nov.
No full textSmiliorachis nubilis (Goding, 1930) comb. nov. Dysyncritus nubilis Goding, 1930 b: 13; Funkhouser, 1951 a: 84; Metcalf & Wade, 1965 a: 645; McKamey, 1998 a: 162. Examined material. Holotype female from BRAZIL: Mato Grosso: Chapada dos Guimarães, ‘Nov.’, ‘Chapada’, ‘Ac- 23739 ’, ‘Am[erican]. Mus[eum]. [of] Nat[ural]. Hist[ory]. \ Dep[ar]t[ment]. [of] Invert[erbrate]. Zool[ogy]. \ No.’, ‘Deitz Research \ 72–81 c’, ‘Dysncritus \ nubilis \ Type Godg.’, ‘ Holotype \ Dysyncritus \ nubilis \ Goding’ (AMNH). Additional material from BRAZIL: Goiás: Leopoldo de Bulhões, ‘ XII. 1933 Goyaz \ Leop-Bulhões \ Coll. R. Spitz’, ‘Coleção \ Pinto da \ Fonseca’ 0 1 female (MZSP). Minas Gerais: Uberaba, ‘Uberaba \ Bresil’, ‘Le Moult’, ‘Deitz Research \ 70–201 i ♀’, ‘ Dysyncritus \ nubilis \ God. \ det. Z.P.M.’ (01 female) (NCSU); ‘Brésil—Uberaba \ Minas Geraes \ Coll. Le Moult’, ‘ Dysyncritus \ nubilis \ God. \ det. Z.P.M.’ (01 male) (NCSU).Published as part of Evangelista, Olivia, Flórez-V, Camilo & Sakakibara, Albino M., 2014, The identity of the treehopper genus Dysyncritus Fowler, with descriptions of new related taxa (Hemiptera: Membracidae: Heteronotinae), pp. 495-532 in Zootaxa 3847 (4) on page 530, DOI: 10.11646/zootaxa.3847.4.2, http://zenodo.org/record/24992
A phosphatidylinositol 3-Kinase-Pax3 axis regulates Brn-2 expression in melanoma
No full textDeregulation of transcription arising from mutations in key signaling pathways is a hallmark of cancer. In melanoma, the most aggressive and lethal form of skin cancer, the Brn-2 transcription factor (POU3F2) regulates proliferation and invasiveness and lies downstream from mitogen-activated protein kinase (MAPK) and Wnt/β-catenin, two melanoma-associated signaling pathways. In vivo Brn-2 represses expression of the microphthalmia-associated transcription factor, MITF, to drive cells to a more stem cell-like and invasive phenotype. Given the key role of Brn-2 in regulating melanoma biology, understanding the signaling pathways that drive Brn-2 expression is an important issue. Here, we show that inhibition of phosphatidylinositol 3-kinase (PI3K) signaling reduces invasiveness of melanoma cells in culture and strongly inhibits Brn-2 expression. Pax3, a transcription factor regulating melanocyte lineage-specific genes, directly binds and regulates the Brn-2 promoter, and Pax3 expression is also decreased upon PI3K inhibition. Collectively, our results highlight a crucial role for PI3K in regulating Brn-2 and Pax3 expression, reveal a mechanism by which PI3K can regulate invasiveness, and imply that PI3K signaling is a key determinant of melanoma subpopulation diversity. Together with our previous work, the results presented here now place Brn-2 downstream of three melanoma-associated signaling pathways. © 2012, American Society for Microbiology
The ISWI and CHD1 chromatin remodeling activities influence ADH2 expression and chromatin organization.
No full textTbx3 represses E-cadherin expression and enhances melanoma invasiveness.
No full textThe T-box transcription factors Tbx2 and Tbx3 are overexpressed in many cancers and in melanoma promote proliferation by actively suppressing senescence. Whether they also contribute to tumor progression via other mechanisms is not known. Here, we identify a novel role for these factors, providing evidence that Tbx3, and potentially Tbx2, directly repress the expression of E-cadherin, a keratinocyte-melanoma adhesion molecule whose loss is required for the acquisition of an invasive phenotype. Overexpression of Tbx2 and Tbx3 in melanoma cells down-regulates endogenous E-cadherin expression, whereas depletion of Tbx3, but not Tbx2, increases E-cadherin mRNA and protein levels and decreases melanoma invasiveness in vitro. Consistent with these observations, in melanoma tissue, Tbx3 and E-cadherin expression are inversely correlated. Depletion of Tbx3 also leads to substantial up-regulation of Tbx2. The results suggest that Tbx2 and Tbx3 may play a dual role during the radial to vertical growth phase transition by both inhibiting senescence via repression of p21(CIP1) expression, and enhancing melanoma invasiveness by decreasing E-cadherin levels
The retinoblastoma protein modulates Tbx2 functional specificity
No full textTbx2 is a member of a large family of transcription factors defined by homology to the T-box DNA-binding domain. Tbx2 plays a key role in embryonic development, and in cancer through its capacity to suppress senescence and promote invasiveness. Despite its importance, little is known of how Tbx2 is regulated or how it achieves target gene specificity. Here we show that Tbx2 specifically associates with active hypophosphorylated retinoblastoma protein (Rb1), a known regulator of many transcription factors involved in cell cycle progression and cellular differentiation, but not with the Rb1-related proteins p107 or p130. The interaction with Rb1 maps to a domain immediately carboxy-terminal to the T-box and enhances Tbx2 DNA binding and transcriptional repression. Microarray analysis of melanoma cells expressing inducible dominant-negative Tbx2, comprising the T-box and either an intact or mutated Rb1 interaction domain, shows that Tbx2 regulates the expression of many genes involved in cell cycle control and that a mutation which disrupts the Rb1-Tbx2 interaction also affects Tbx2 target gene selectivity. Taken together, the data show that Rb1 is an important determinant of Tbx2 functional specificity
MITF controls the TCA cycle to modulate the melanoma hypoxia response
No full textIn response to the dynamic intra-tumor microenvironment, melanoma cells adopt distinct phenotypic states associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia is driven by hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote angiogenesis. HIF1α indirectly represses MITF that can activate HIF1α expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they co-regulate subset of target genes. Moreover, the genomewide impact of hypoxia on melanoma and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 hr in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1α and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma
Organelle-autonomous regulation of size and number: OA1 receptor sustains Pmel17 expression
No full textOne of the main themes of cell biology is the regulation of intracellular organelles number and the correct size preservation. Melanosome biogenesis is a good example of organelle maturation, and the Ocular Albinism type I, that displays a specific morphological phenotype characterized by enlarged melanosomes in the Retinal Pigment Epithelium and in the skin melanocytes, is an useful model to clarify some of these aspects. In this disease, the macromelanosome represents the abnormal growth of a single organelle. Our studies provide a potential molecular mechanism about the role of OA1 protein concerning the control of melanosome size and number.OA1 influences Mitf transcription amount. In Oa1 knockout melanocytes, as well as in silenced cells, the considerable decrease of Mitf does not determine a pigmentation gross alteration, but it provokes anabnormal expression of PMEL17, a key protein of the melanosome biogenesis. With these results, we found evidences that the control of melanin synthesis and of the rate of new melanosome biogenesis rely on different independent control factors
A polymorphism in the agouti signalling protein (ASIP) is associated with decreased levels of mRNA
No full textTo date, a role for agouti signalling protein (ASIP) in human pigmentation has not been well characterized. It is known that agouti plays a pivotal role in the pigment switch from the dark eumelanin to the light pheomelanin in the mouse. However, because humans do not have an agouti banded hair pattern, its role in human pigmentation has been questioned. We previously identified a single polymorphism in the 3'-untranslated region (UTR) of ASIP that was found at a higher frequency in African-Americans compared with other population groups. To compare allele frequencies between European-Australians and indigenous Australians, the g.8818A -> G polymorphism was genotyped. Significant differences were seen in allele frequencies between these groups (P < 0.0001) with carriage of the G allele highest in Australian Aborigines. In the Caucasian sample set a strong association was observed between the G allele and dark hair colour (P = 0.004) (odds ratio 4.6; 95% CI 1.4-15.27). The functional consequences of this polymorphism are not known but it was postulated that it might result in message instability and premature degradation of the transcript. To test this hypothesis, ASIP mRNA levels were quantified in melanocytes carrying the variant and non-variant alleles. Using quantitative real-time polymerase chain reaction the mean ASIP mRNA ratio of the AA genotype to the AG genotype was 12 (P < 0.05). This study suggests that the 3'-UTR polymorphism results in decreased levels of ASIP and therefore less pheomelanin production
Organelle-autonomous regulation of size and number: OA1 receptor sustains Pmel17 expression
No full textOne of the main themes of cell biology is the regulation of intracellular organelles number and the correct size preservation. Melanosome biogenesis is a good example of organelle maturation, and the Ocular Albinism type I, that displays a specific morphological phenotype characterized by enlarged melanosomes in the Retinal Pigment Epithelium and in the skin melanocytes, is an useful model to clarify some of these aspects. In this disease, the macromelanosome represents the abnormal growth of a single organelle. Our studies provide a potential molecular mechanism about the role of OA1 protein concerning the control of melanosome size and number.
OA1 influences Mitf transcription amount. In Oa1 knockout melanocytes, as well as in silenced cells, the considerable decrease of Mitf does not determine a pigmentation gross alteration, but it provokes an
abnormal expression of PMEL17, a key protein of the melanosome biogenesis. With these results, we found evidences that the control of melanin synthesis and of the rate of new melanosome biogenesis rely on different independent control factors
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