Hee-Young Park's research while affiliated with Boston University and other places
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Publications (40)
Hyperpigmentation disorders are generally difficult to treat because of the limited availability of effective therapeutics with minimal side effects. In this issue, Lehraiki et al. report that metformin, an antidiabetic drug, inhibited melanogenesis, in vitro and in vivo, and they suggest that metformin may be used to treat hyperpigmentation disord...
Dysregulation of the CXCR4/CXCL12 axis, relevant in melanoma progression, activates cell cycle progression and migration via stimulation of the MAPK-pathway. We sought to ascertain the cooperativity of the CXCR4/CXCL12 axis with established prognosticators and BRAF status in melanoma. Samples (n=107) of primary cutaneous melanoma were assessed for...
Dysregulation of the chemokine receptor CXCR4 is relevant in melanoma progression, and the CXCR4/CXCL12 axis has been shown to activate cell cycle progression and malignant cell migration through stimulation of the mitogen-activated protein kinase pathway. Studies ascertaining the potential utility of CXCR4 mRNA as a prognosticator in melanoma have...
Cutaneous pigmentation or skin color is the body's natural protection against sun-induced damage. Skin color is determined primarily by melanin, a biopolymer that is synthesized within epidermal melanocytes, packaged in cellular organelles called melanosomes, and then dispersed to neighboring keratinocytes. The process of melanogenesis involves num...
Melanocytes are pigment-producing cells that originate from the dorsal portions of the closing neural tube in vertebrate embryos. Similar to neurons, they are derived from pluripotent neural crest cells that differentiate into numerous cell lineages. The development of melanocytes and neurons, as well as their differentiated function, within the ma...
Protein kinase C (PKC) is a multigene family of serine/threonine protein kinases involved in cell signaling pathways of proliferation and motility. PKC interacts with Rho GTPases in the regulation of the actin cytoskeleton. The PKC-alpha isozyme binds the Rho GTPase cdc42, and both are coordinated with the Rac-phosphatidylinositol-3 kinase (PI3K) s...
Bone Morphogenetic Protein (BMP-4) was shown to down-regulate melanogenesis, in part, by decreasing the level of tyrosinase [Yaar et al. (2006) JBC:281]. Results presented here show that BMP-4 down-regulated the protein levels of TRP-1, PKC-beta, and MCI-R. When paired cultures of human melanocytes were treated with vehicle or BMP-4 (25 ng/ml), MAP...
Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta family, signal in many cells including neural precursors. Two receptors, types 1 and 2, coordinately mediate BMP signaling, and type 1 receptor has two forms: A and B. Using RT-PCR we found that neural crest-derived human melanocytes express BMP receptor-1A, -1B, and...
The cAMP-dependent pathway up-regulates MITF (microphthalmia-associated transcription factor), important for key melanogenic proteins such as tyrosinase, TRP-1 (tyrosinase-related protein 1) and TRP-2. We asked whether MITF is also a key transcription factor for PKC-beta (protein kinase C-beta), required to phosphorylate otherwise inactive tyrosina...
Vascular endothelial growth factor (VEGF) is constitutively produced by keratinocytes, but has no known epidermal target cell. We now report that normal human melanocytes (Mc) maintained in serum-free, hormone-, and growth factor-supplemented medium lacking phorbol ester and choleragen constitutively express VEGF receptor-1 (VEGFR-1), VEGFR-2, and...
Wound fluid collected from chronic venous leg ulcers (chronic wound fluid (CWF)) has been shown to inhibit the growth of dermal fibroblasts by interfering with cell-cycle progression from G1 into S phase. Specifically, CWF was shown to downregulate the levels of hyperphosphorylated retinoblastoma tumor-suppressor gene (Rb) and cyclin D1, known to b...
Protein kinase C (PKC), a family of at least eleven isoforms, mediates numerous cell functions. In human melanocytes, alpha, beta, delta, epsilon and zeta isoforms of PKC are expressed, but uniquely PKC-beta activates tyrosinase, the key and the rate-limiting enzyme in melanogenesis, by phosphorylating specific serine residues on its cytoplasmic do...
To determine whether inhibition of PKC-beta activity decreases pigmentation, paired cultures of primary human melanocytes were first pretreated with bisindolylmaleimide (Bis), a selective PKC inhibitor, or vehicle alone for 30 min, and then treated with TPA for an additional 90 min to activate PKC in the presence of Bis. Bis blocked the expected in...
Tyrosinase, the key enzyme in melanogenesis, is activated when protein kinase C-beta (PKC-beta) phosphorylates the serine residues at amino acid positions 505 and 509. To further elucidate the mechanism by which phosphorylation of tyrosinase by PKC-beta leads to the activation of tyrosinase, a possible complex formation between phosphorylated tyros...
Microphthalmia-associated transcription factor (MITF), a basic-helix-loop-helix (bHLH) and bHLH-leucine zipper transcription factor, is currently an intense focal point in pigment cell biology research. MITF is implicated as the master gene for survival of melanocytes, as well as a key transcription factor regulating the expression of major melanog...
Melanogenesis, or synthesis of melanin has been a focus of intense investigation by pigment cell biologists during the past few decades. Melanogenesis provides pigment in skin, thus serving as a unique, if not only, physiological defense against sun-induced injuries, including photocarcinogenesis. Moreover, skin color plays a major role in visual e...
Fibroblasts (fb) play an important role in wound healing involving motility, contraction, fibrosis, and expression of the cytoskeletal protein alpha-smooth muscle actin (alpha-sma). Patients with chronic venous insufficiency (CVI) are known to have dermal changes and impaired venous ulcer healing. To investigate whether these dermal-fb have an alte...
Acute wound healing has been extensively investigated over the years, however, little is known about possible healing defects in chronic wounds. Fibronectin (FN) plays a critical role in different phases of wound healing and has been demonstrated to be degraded in chronic wounds by proteases. Fibroblasts cultured from chronic leg ulcers showed a hi...
We have previously shown that fibroblasts cultured from venous ulcers display characteristics of senescence and have reduced growth rates. Susceptibility of young fibroblasts to the microcirculatory changes associated with venous ulcers, such as macrophage trapping and activation, could explain the prevalence of senescent fibroblasts in these wound...
Background:
Fibroblasts (fb) cultured from venous ulcer patients and patients with venous reflux disease without ulcer demonstrate characteristics of cellular senescence, such as increased fibronectin level and senescence-associated beta-galactosidase (SA beta-gal) positive cells. Cellular senescence is an in vitro event characterized by the progr...
We have previously shown that protein kinase C-beta (PKC-beta) is required for activation of tyrosinase (Park, H. Y., Russakovsky, V., Ohno, S., and Gilchrest, B. A. (1993) J. Biol. Chem. 268, 11742-11749), the rate-limiting enzyme in melanogenesis. We now examine its mechanism of activation in human melanocytes. In vivo phosphorylation experiments...
It is known that chronic wounds such as leg ulcers have an increased risk of malignant transformation, mainly to squamous cell carcinoma (reviewed in Reference 1).
To better understand the molecular changes responsible for this increased risk of malignant transformation, we examined the expression of c-fos and c-Ha-ras, proto-oncogenes known to be...
A well-recognized characteristic of venous ulcers is impaired healing. Fibroblasts cultured from venous ulcers (wound-fb) have been shown to have reduced growth rates and are larger than normal fibroblasts (normal-fb) from the ipsilateral limb. Reduced growth capacity and morphologic changes are 2 well-known traits of cellular senescence. Other mol...
Venous reflux precedes the development of venous ulcers. Our earlier work showed that the fibroblasts that are cultured from these wounds display more characteristics of senescence. We evaluated fibroblast senescence in patients with venous reflux but without ulcers to further investigate the role of venous reflux in the predisposition to venous ul...
The cAMP-dependent pathway has been long presumed to play a critical role in mediating alpha-melanocyte-stimulating hormone (alpha-MSH)-induced pigmentation, but it has never been demonstrated that this pathway is obligatory. In order to determine whether the cAMP-dependent pathway is required for a alpha-MSH-induced pigmentation, we inhibited the...
Human dermal fibroblasts are known to express the alpha, delta, epsilon, and zeta isoforms of protein kinase C (PKC). We asked whether the growth of human dermal fibroblasts correlates with expression of a particular PKC isoform. Of total PKC activity measured in the presence of calcium, a condition permissive for activation of all PKC isoforms, 75...
Protein kinase C (PKC) is a multigene family of at least 12 isoforms involved in the transduction of extracellular signals. We investigated whether PKC-α, a major isoform known to be relatively abundant in brain tissue, is increased in human melanocytes relative to keratinocytes in vitro and in situ.
Immunohistochemical staining for PKC-α in frozen...
Although the slow healing rate of venous ulcers is well known, the underlying defect in the healing process is not well understood. The purpose of this study was to examine the cellular characteristics of fibroblasts taken from venous ulcers (wound-fb) and compare them with the fibroblasts of normal tissue (normal-fb).
Biopsy specimens were obtaine...
We have explored the role of protein kinase C (PKC) in pigmentation induced by alpha-melanocyte stimulating hormone (alpha-MSH). Using the well-studied S91 Cloudman mouse melanoma model system in which 10(-7) M alpha-MSH is known to produce a time-dependent increase in pigmentation, we found an increase in the activity of tyrosinase, the key enzyme...
Background
Murine melanoma cells such as Cloudman S91 or B16 mouse melanoma cells have been used extensively to study mechanisms involved in pigmentation because these cells have tyrosinase, the key enzyme in pigmentation, and produce pigment. We have observed that serial passaged S91 cells tend to decrease their basal pigment content and to lose t...
Work in the past 8 years, particularly in the past 1-2 years, has greatly expanded our understanding of the mechanisms by which ultraviolet irradiation stimulates melanogenesis in the skin. A direct effect of UV photons on DNA results in up-regulation of the gene for tyrosinase, the rate-limiting enzyme in melanin synthesis, as well as an increase...
The link between sun exposure and skin cancer is well established, but the mechanism of photocarcinogenesis is still incompletely understood. In vitro experimentation has shown that induction of the c-fos proto-oncogene occurs in cultured human keratinocytes after ultraviolet exposure, and c-Ha-ras mutations are commonly present in human skin neopl...
The protein kinase C (PKC) family of proteins, consisting of at least ten isoforms, has been shown to regulate major cellular functions, including the growth and differentiation in many cell types. Use of PKC activators and inhibitors in combination with molecular biology techniques, has permitted detailed exploration of their specific intracellula...
In testing the hypothesis that the stimulation of the release of fibronectin (FN) by 12-O-tetradecanoylphorbol 13-acetate (TPA) from human lung fibroblasts in culture is the result of activation of protein kinase C (PKC), we found that the PKC inhibitor sphingosine strongly inhibited FN release in presence and even in absence of TPA. However, a dif...
Citations
... Our laboratory has determined that protein kinase C-b (PKC-b) activates tyrosinase (Park et al, 1993), the key and the rate-limiting enzyme in pigmentation (Pawelek and Chakraborty, 1998), by phosphorylating serine residues at amino acid positions 505 and 509 . Loss of PKC-b prevents melanogenesis in cultured pigment cells (Yamanishi et al, 1991;Powell et al, 1993;Yamanishi and Meyskens, 1994;Park and Gilchrest, 1996;, suggesting that inhibition of this isoform specifically or as part of pan-PKC inhibition might lead to skin and hair lightening in vivo. ...
... Therefore, the search for an effective therapy that achieves depigmentation with no side effects has continued. Studies demonstrated that topical metformin has melanopenic effect because of down regulation of MITF expression leading to downregulation of several melanogenic proteins including tyrosinase, tyrosinase related protein-1(TRP-1), TRP-2, and protein kinase Cbeta (9)(10)(11) . ...
... Immunohistochemistry and genetic studies, as well as analyses of patient serum, have highlighted these differences and could be incorporated to aid diagnosis. For example, malignant melanomas express higher levels of CXCL1, CXCL2, and CXCL8 and receptors CXCR1, CXCR4, CCR10, and CCR7 compared with benign naevi [108][109][110][111]. The expression of chemokines such as CXCL8 and its receptor CXCR2 increase as the tumour transitions from the radial to the vertical growth phase [24]. ...
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... Immunohistochemistry and genetic studies, as well as analyses of patient serum, have highlighted these differences and could be incorporated to aid diagnosis. For example, malignant melanomas express higher levels of CXCL1, CXCL2, and CXCL8 and receptors CXCR1, CXCR4, CCR10, and CCR7 compared with benign naevi [108][109][110][111]. The expression of chemokines such as CXCL8 and its receptor CXCR2 increase as the tumour transitions from the radial to the vertical growth phase [24]. ...
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... [55][56][57] In normal melanocytes, cAMP increases PKC-expression, which then phosphorylates and stimulates tyrosinase. 58 This crosstalk could also be a possible pathway for PKC activation in SK-Mel 23 cells. ...
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... Nevertheless, most of inhibitory capacity on MMP-1 activity study can be found commonly in plant samples such as white tea, green tea, persimmon leaf, Sanguisorba officinalis and flavonoids [5,[29][30][31] . On the other perspective, according to Park, et al. [32] peptides especially tyrosine peptides could inhibit tyrosinase enzyme by oxidation of L-3,4-dihydroxyphenylalanine in competitive inhibition. This process enhances the pigmentation decomposition resulting in lighter skin. ...
... The dermis, on the other hand, is densely packed with fibroblasts that secrete a variety of structural components with significant reparative and wound-healing properties. Furthermore, this layer contributes to the regulation of extracellular matrices as well as interstitial fluid volume [7]. ...
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... -3 of 14 molecules, receptors and signalling pathways with cells of the nervous system. [35][36][37] Additionally, although the underlying pathophysiological mechanisms are not fully understood, the skin and brain are anatomically and functionally connected (skin-brain axis) via a complex interplay between the skin and the nervous, endocrine and immune systems, with both central (systemic) and peripheral (local) pathways playing a role to modulate the response. 15 Activation of these pathways influences the skin's immune system, barrier function, wound healing and susceptibility to infection. ...
... In fact, PKC signaling regulates Rho GTPases involved in the formation of promotility actin-rich peripheral protrusions (e.g. lamellipodia, ruffles) and stress fibers (29,30,49,(53)(54)(55). Dissecting PKCα downstream effectors is key to untangle the molecular basis of these regulatory processes. ...
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... BMP signalling is influenced by the BMP type, presence of antagonists, development stage of the target tissue, and target cell receptors. Keratinocytes and melanocytes express BMP4 and BMP6, their receptors (serine/threonine kinase receptors type I and II, BMPR1 and BMPR2), and the respective antagonists, sclerostin and noggin, altogether affecting the production of melanin (Figure 8) [50,[389][390][391][392]. BMP6 has been shown to stimulate melanogenesis by upregulating tyrosinase expression and activity; additionally, it also stimulates the formation of filopodia and MYO10 expression, associated with increased melanosome transfer from melanocytes to keratinocytes. ...
