Activation of melanogenesis by vacuolar type H<sup>+</sup>‐ATPase inhibitors in amelanotic, tyrosinase positive human and mouse melanoma cells

Ancans, Janis; Thody, A. J.

doi:10.1016/s0014-5793(00)01795-6

Cited by 51 publications

(40 citation statements)

References 34 publications

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“…Our results are in agreement with previous reports demonstrating that melanin synthesis was stimulated by agents that increase melanosome pH. This is true for the lysosomotropic compound, ammonium chloride, ionophores such as nigericin and monensin, and inhibitors of the vacuolar ATPases such as bafilomycin (26,27). Fuller et al (28) reported that the melanosomes of melanocytes from Caucasian skin displayed low tyrosinase activity and were more acidic than the melanosomes of melanocytes from black skin, which had high tyrosinase activity.…”

Section: Discussionsupporting

confidence: 93%

αMSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism

Chéli

Luciani

Khaled

et al. 2009

Journal of Biological Chemistry

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Melanins are synthesized in melanocytes within specialized organelles called melanosomes. Numerous studies have shown that the pH of melanosome plays a key role in the regulation of melanin synthesis. However, until now, acute regulation of melanosome pH by a physiological stimulus has never been demonstrated. In the present study, we show that the activation of the cAMP pathway by ␣MSH or forskolin leads to an alkalinization of melanosomes and a concomitant regulation of vacuolar ATPases and ion transporters of the solute carrier family. The solute carrier family members include SLC45A2, which is mutated in oculocutaneous albinism type IV, SLC24A4 and SLC24A5, proteins implicated in the control of eye, hair, and skin pigmentation, and the P protein, encoded by the oculocutaneous albinism type II locus. Interestingly, H89, a pharmacological inhibitor of protein kinase A (PKA), prevents the cAMP-induced pigmentation and induces acidification of melanosomes. The drastic depigmenting effect of H89 is not due to an inhibition of tyrosinase expression. Indeed, H89 blocks the induction of melanogenesis induced by LY294002, a potent inhibitor of the PI 3-kinase pathway, without any effect on tyrosinase expression. Furthermore, PKA is not involved in the inhibition of pigmentation promoted by H89 because LY294002 induces pigmentation independently of PKA. Also, other PKA inhibitors do not affect pigmentation. Taken together, our results strengthen the support for a key role of melanosome pH in the regulation of melanin synthesis and, for the first time, demonstrate that melanosome pH is regulated by cAMP and ␣MSH. Notably, these are both mediators of the response to solar UV radiation, the main physiological stimulus of skin pigmentation.

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Section: Discussionsupporting

confidence: 93%

αMSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism

Chéli

Luciani

Khaled

et al. 2009

Journal of Biological Chemistry

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“…For instance, melanosomes and lysosomes contain many of the same structural proteins (e.g. LAMP, acidic hydrolases, vacuolar-type proton pumps (47,74,75)), and both are affected in several genetic disorders, such as the Chediak-Higashi and Hermansky-Pudlak syndromes (76,77). The catalytic domains of TYR and other enzymes involved in melanogenesis are located within the lumen of the melanosome, and it follows that their activity is likely to be dependent upon the intramelanosomal environment, including the pH (19).…”

Section: Discussionmentioning

confidence: 99%

“…It has been assumed that this low melanosomal pH facilitates melanogenesis (44 -46). Recently, the activation of melanogenesis by selective vacuolar type proton pump inhibitors, bafilomycin A1 (Baf) and concanamycin A (CCM), was shown in amelanotic human melanoma cells and in mouse melanoma cells, which express TYR but do not produce pigment (47). Further, Baf and CCM induce melanin synthesis in pink-eyed dilution gene (p)-null melanocytes by affecting early TYR processing and trafficking rather than by simply affecting activity at the melanosomal level (48,49).…”

mentioning

confidence: 99%

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Watabe

Valencia

Yasumoto

et al. 2004

Journal of Biological Chemistry

122

105

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Pigmentation of the hair, skin, and eyes of mammals results from a number of melanocyte-specific proteins that are required for the biosynthesis of melanin. Those proteins comprise the structural and enzymatic components of melanosomes, the membrane-bound organelles in which melanin is synthesized and deposited. Tyrosinase (TYR) is absolutely required for melanogenesis, but other melanosomal proteins, such as TYRP1, DCT, and gp100, also play important roles in regulating mammalian pigmentation. However, pigmentation does not always correlate with the expression of TYR mRNA/protein, and thus its function is also regulated at the post-translational level. Thus, TYR does not necessarily exist in a catalytically active state, and its post-translational activation could be an important control point for regulating melanin synthesis. In this study, we used a multidisciplinary approach to examine the processing and sorting of TYR through the endoplasmic reticulum (ER), Golgi apparatus, coated vesicles, endosomes and early melanosomes because those organelles hold the key to understanding the trafficking of TYR to melanosomes and thus the regulation of melanogenesis. In pigmented cells, TYR is trafficked through those organelles rapidly, but in amelanotic cells, TYR is retained within the ER and is eventually degraded by proteasomes. We now show that TYR can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which TYR is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system. The expression of TYRP1, which facilitates TYR processing in the ER, is down-regulated in the amelanotic cells; this is analogous to a hypopigmentary disease known as oculocutaneous albinism type 3 and further impairs melanin production. The sum of these results shows that organellar pH, proteasome activity, and down-regulation of TYRP1 expression all contribute to the lack of pigmentation in TYRpositive amelanotic melanoma cells.

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“…Tyrosinase, the rate-limiting enzyme in melanogenesis, exhibits optimal enzymatic activity at neutral pH but is almost completely inactive at acidic pH (Hearing and Ekel 1976;Ancans et al 2001b). Further, selective V-ATPase inhibitors (bafilomycin A1 and concanamycin A) or ionophores that dissipate the proton gradient stimulate melanogenesis Oikawa 1983, 1985;Oikawa et al 1987;Ancans and Thody 2000;Halaban et al 2002;, implying an anti-melanogenic role for luminal acidification. These observations indicate that the acidification inside melanosomes is inhibitory for melanogenesis (Ancans et al 2001a(Ancans et al , 2001b.…”

Section: Introductionmentioning

confidence: 99%

Vacuolar-type H+-ATPase with the a3 isoform is the proton pump on premature melanosomes

et al. 2008

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The melanosome, an organelle specialized for melanin synthesis, is one of the lysosome-related organelles. Its lumen is reported to be acidified by vacuolar-type H(+)-ATPase (V-ATPase). Mammalian V-ATPase exhibits structural diversity in its subunit isoforms; with regard to membrane intrinsic subunit a, four isoforms (a1-a4) have been found to be localized to distinct subcellular compartments. In this study, we have shown that the a3 isoform is co-localized with a melanosome marker protein, Pmel17, in mouse melanocytes. Acidotropic probes (LysoSensor and DAMP) accumulate in non-pigmented Pmel17-positive melanosomes, and DAMP accumulation is sensitive to bafilomycin A1, a specific inhibitor of V-ATPase. However, none of the subunit a isoforms is associated with highly pigmented mature melanosomes, in which the acidotropic probes are also not accumulated. oc/oc mice, which have a null mutation at the a3 locus, show no obvious defects in melanogenesis. In the mutant melanocytes, the expression of the a2 isoform is modestly elevated, and a considerable fraction of this isoform is localized to premature melanosomes. These observations suggest that the V-ATPase keeps the lumen of premature melanosomes acidic, whereas melanosomal acidification is less significant in mature melanosomes.

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Activation of melanogenesis by vacuolar type H⁺‐ATPase inhibitors in amelanotic, tyrosinase positive human and mouse melanoma cells

Cited by 51 publications

References 34 publications

αMSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism

αMSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Vacuolar-type H+-ATPase with the a3 isoform is the proton pump on premature melanosomes

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Activation of melanogenesis by vacuolar type H+‐ATPase inhibitors in amelanotic, tyrosinase positive human and mouse melanoma cells

Cited by 51 publications

References 34 publications

αMSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism

αMSH and Cyclic AMP Elevating Agents Control Melanosome pH through a Protein Kinase A-independent Mechanism

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Vacuolar-type H+-ATPase with the a3 isoform is the proton pump on premature melanosomes

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Activation of melanogenesis by vacuolar type H⁺‐ATPase inhibitors in amelanotic, tyrosinase positive human and mouse melanoma cells