Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of <scp>MITF</scp> via <scp>ROS</scp>‐<scp>ERK</scp> activation

Kim, Eun Sung; Park, Soo‐Young; Goh, Myeong-Jin; Na, Yongjoo; Jo, Doo Sin; Jo, Yoon Kyung; Shin, Ji Hyun; Choi, Eun Sun; Lee, Haekwang; Kim, Ju‐Yeon; Jeon, Hong Bae; Kim, Jin Cheon; Cho, Dong‐Hyung

doi:10.1111/pcmr.12298

Cited by 53 publications

(50 citation statements)

References 48 publications

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“…It is known that Mitf expression is regulated by MAPK signaling [45], and we therefore focused on this pathway. Intriguingly, there is evidence suggesting that the MAPK pathway can be influenced by copper, through the finding that copper can enhance the MEK1/2-dependent phosphorylation of ERK1/2, leading to enhanced proteasomal degradation of Mitf [37].…”

Section: Discussionmentioning

confidence: 99%

Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells

Frisk

Kjellén

Kaler

et al. 2017

The Journal of Immunology

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Copper has previously been implicated in the regulation of immune responses, but the impact of this metal on mast cells is poorly understood. Here, we address this issue and show that copper starvation of mast cells causes increased granule maturation as indicated by higher proteoglycan content, stronger metachromatic staining and altered ultrastructure in comparison with non-treated cells, whereas copper overload has opposite effects. In contrast, copper status did not impact storage of histamine in mast cells, nor did alterations in copper levels affect the ability of mast cells to degranulate in response to IgE receptor crosslinking. A striking finding was decreased tryptase content in mast cells with copper overload, whereas copper starvation increased tryptase content. These effects were associated with corresponding shifts in tryptase mRNA levels, suggesting that copper affects tryptase gene regulation. Mechanistically, we found that alterations in copper status affected the expression of Mitf, a transcription factor critical for driving tryptase expression. We also found evidence supporting the concept that the effects on Mitf are dependent on copper-mediated modulation of MAPK signaling. Finally, we show that in MEDNIK syndrome, a condition associated with low copper levels and a hyper-allergenic skin phenotype including pruritis and dermatitis, the number of tryptase-positive mast cells is increased. Taken together, our findings reveal a hitherto unrecognized role for copper in regulation of mast cell gene expression and maturation.

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Section: Discussionmentioning

confidence: 99%

Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells

Frisk

Kjellén

Kaler

et al. 2017

The Journal of Immunology

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“…Microphthalmia transcription factor specifically binds to the M‐box and E‐box motifs of Tyr , TRP1 , and TRP2 and upregulates their expression (Bertolotto et al ., ). Our results showed an increase in the expression of MITF upon Sak treatment and reach its maximum after 24 h. Studies have shown that the MAP kinases signaling pathways (ERK, JNK, and p38) are involved in the regulation of MITF activity (Bu et al ., ; Ye et al ., ; Kim et al ., ). Activation of ERK MAP kinases induces the phosphorylation of MITF at Ser 73, and together with recruitment of the transcriptional coactivator p300, this process leads to ubiquitination and proteasome‐mediated degradation of MITF.…”

Section: Discussionmentioning

confidence: 97%

Sakuranetin Induces Melanogenesis in B16BL6 Melanoma Cells through Inhibition of ERK and PI3K/AKT Signaling Pathways

Drira

Sakamoto

2016

Phytother. Res.

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Sakuranetin (Sak) is considered one of the most important flavanone phytoalexins in regard to antimicrobial activity, and accumulation, in the rice plant. The current study determined that Sak strongly stimulates melanogenesis in B16BL6 melanoma cells in a dose-dependent manner. This flavonoid upregulates the expression of microphthalmia transcription factor (MITF) and reaches its maximum after 24 h. In addition, Sak was found to increase in vitro tyrosinase (Tyr) activity, along with time-dependent upregulation of Tyr, tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2). Sakuranetin also decreased the proliferation rate in these cells without directly affecting their viability, as revealed by MTT and trypan blue assays. Further, Sak was shown to inhibit phosphorylation and activation of ERK1/2 from 12 h, without significantly affecting p38 and JNK phosphorylation. Sakuranetin was also found to inhibit the phosphorylation of AKT at threonine 308 and serine 473 and leads to activation of GSK3β via decreased phosphorylation at serine 9. Taken together, these results demonstrate that Sak stimulates melanogenesis in B16 melanoma cells via inhibition of ERK1/2 and PI3K/AKT signaling pathways, which lead to upregulation of Tyr, TRP1, and TRP2. Copyright © 2016 John Wiley & Sons, Ltd.

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“…As expected, our results showed that MTFP1 significantly increased the phosphorylation of DRP1 at Ser616, while decreased the phosphorylation of DRP1 at Ser637, which subsequently facilitated the fragmentation of mitochondrial in OSCC cells. A body of evidence has indicated the association between increased mitochondria fission and production of ROS (Kim et al, ; Wang et al, ; Huang et al, ), which contributes to tumor cell growth by inducing genomic instability and participating in signaling pathways (Yang et al, ; de Sa Junior et al, ; Prasad et al, ; Moloney and Cotter, ). Our results showed a dramatic induction of ROS production and activation of Akt signaling by MTFP1 in OSCC cells.…”

Section: Discussionmentioning

confidence: 99%

MTFP1 overexpression promotes the growth of oral squamous cell carcinoma by inducing ROS production

Xiao

Sun

Xing

et al. 2019

Cell Biology International

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Mitochondrial fission process 1 (MTFP1) is a novel nuclear‐encoded protein that promotes mitochondrial fission. Increasing lines of evidence indicate that increased mitochondrial fission is involved in carcinogenesis and tumor progression. However, the expression and biological effects of MTFP1 in cancer development is still unclear, especially in oral squamous cell carcinoma (OSCC). In this study, we first evaluated the expression of MTFP1 in 12‐paired OSCC tumor and peritumor tissues. We then explored the effects of MTFP1 knockdown or overexpression on cell growth by cell proliferation, colony formation, cell cycle, and cell apoptosis assays. Furthermore, the mechanisms by which MTFP1 promoted OSCC cell growth were explored. Our results showed that MTFP1 is frequently overexpressed in OSCC tissues. Functional experiments revealed that MTFP1 promoted the growth of OSCC cells by inducing the progression of cell cycle and suppressing cell apoptosis. Mechanistically, MTFP1 overexpression‐mediated mitochondrial fragmentation and subsequent ROS production was found to be involved in the promotion of OSCC cell growth. Collectively, our study demonstrates that MTFP1 plays a critical oncogenic role in OSCC carcinogenesis, which may serve as a potential therapeutic target in the treatment of this malignance.

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Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of MITF via ROS‐ERK activation

Cited by 53 publications

References 48 publications

Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells

Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells

Sakuranetin Induces Melanogenesis in B16BL6 Melanoma Cells through Inhibition of ERK and PI3K/AKT Signaling Pathways

MTFP1 overexpression promotes the growth of oral squamous cell carcinoma by inducing ROS production

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