Chapter 72 Biology of Melanocytes Flashcards
_____ are pigment-producing cells that originate from the dorsal portions of the closing neural tube in vertebrate embryos
Melanocytes
derive from pluripotent neural crest cells that differentiate into numerous cell lineages including neurons, glia, smooth muscle, craniofacial bone, cartilage, and melanocytes
Melanocyte stem cells reside in the______
hair follicle bulge
There is approximately one melanocyte per _______
five or six basal keratinocytes
Melanocytes synthesize ______, a pigmented polymer that is stored in cytosolic organelles called ______ that are transferred to keratinocytes through melanocyte dendritic processes
melanin
melanosomes
The term _______ describes a single epidermal melanocyte surrounded by several epidermal keratinocytes
epidermal melanin unit
Melanocyte density/mm2 ranges from approximately 550 to >1,200 with the highest concentrations found in the _______
genitalia and face
Hair
Melanocytes are located in the ______ during anagen and there is a ratio of 1:5 between melanocytes and keratinocytes and 1:1 between melanocytes and basal layer keratinocytes
proximal hair bulb
______ are large (∼0.9 × 0.3 μm), elliptical in shape and contain a highly structured fibrillar glycoprotein matrix required for _____ synthesis
Eumelanosomes
eumelanin
______ are smaller (∼0.7 μm in diameter), spherical in shape and their glycoprotein matrix appears disorganized and loose
Pheomelanosomes
_______ gene maps to chromosome 11. The human tyrosinase gene is composed of five exons and four introns
human tyrosinase
Tyrosinase is synthesized in the ___ as a precursor protein whose nascent chain is processed in the ______ where sialic acid and neutral sugars are added to the peptide via N- and O-glycosidic linkages through a process called _______
ER
Golgi complex
glycosylation
_____ residues present in the inner (catalytic) portion of tyrosinase bind _____ and the latter are required for tyrosinase activity
Histidine
copper (Cu) ions
______ must phosphorylate two serine residues on this cytoplasmic domain to activate tyrosinase, and in the absence of those phosphorylation events pigmentation does not occur
protein kinase C-β (PKC-β)
Tyrosinase mutations including missense, nonsense frameshift, and deletion mutations that lead to inactivation of the enzyme are found in _______
oculocutaneous albinism type I
in human melanocytes, the _______ complex translocates to the melanosome membrane to allow tyrosinase phosphorylation
activated PKC-β/RACK-I
After its synthesis, ____ is transported to stage I melanosomes to form a fibrillar structure that is the backbone of eumelanosome matrix, contributes to melanosome ellipsoid shape and promotes melanin polymerization.
Pmel17
Melanosomes lacking Pmel17 cannot transit to stage II and have no active melanogenesis
________, is a membrane-associated protein that is present in stage I and stage II melanosomes and forms a complex with Pmel17
MART-1, also known as Melan A
Patients with _______,—an autosomal recessive disorder of oculocutaneous albinism, platelet dysfunction, and pulmonary disease have defects in specific subunits of the ______ and as a result display several anomalies associated with cellular transport of molecules
Hermansky–Pudlak syndrome
AP-3 adaptor protein complex
AP-3 and possibly also AP-1 facilitate tyrosinase transport from endosomes to melanosomes
an ATP-associated proton pump responsible for maintaining acidic environment within the mela- nosomes.
Other proposed functions include stabilizing the tyrosinase/TRP-1/TRP-2 complex and/or transporting tyrosine into the melanosome
P-protein
Individuals lacking functional P-protein display occulocutaneous albinism type 2, largely due to improper melanosomal pH.
Also, Angelman and Prader–Willi syndromes display deletion mutations that include the P-locus on chromosome 15
scavengers of free radicals that are produced during melanin biosynthesis
Lysosome-Associated Membrane Proteins
master gene for melanocyte survival and is a key factor regulating the transcription of the major melanogenic proteins, tyrosinase, TRP-1, TRP-2, PKC-β and MART-1.
Microphthalmia-Associated
Transcription Factor
In melanocytes, it is the MITF-M isoform that stimulates transcription of tyrosinase and PKC-b.
MITF activity is increased upon its phosphorylation by the ______, whose activity is in turn induced by binding of SF/kit/stem cell factor to c-Kit receptor
mitogen-activated protein kinase-2 (MAP kinase-2)
Phosphorylated MITF binds to another protein, p300/CBP, which belongs to a coactivator family of proteins and acts to enhance MITF transcriptional activity.
Another kinase that is activated by SF/c-Kit interaction is p90RSK that also phosphorylates MITF but at a different site from that phosphorylated by MAP kinase-2.
expression of MITF is under the control of several transcription factors, including Sox10 (mutated in ______) and Pax3.
Waardenburg’s syndrome type 4
MITF promotes melanoycte survival by upregulating the expression of a major antiapoptotic protein ____
It is frequently overexpressed or amplified in _______, contributing to their increased survival.
Mutations in MITF are found in the pigmentary disorder _______
BCl2
melanomas
Waardenburg syndrome type 2
____ and ______ are mainly found in the central nervous system, are absent in melanocytes, and are thought to control energy intake.
____ is expressed in the adrenal cortex and ____ is expressed in peripheral adipocytes.
____ is expressed in a number of cells such as endothelial cells, fibroblasts, and keratinocytes, but the highest expression is found in melanocytes
MC3R and MC4R
MC2R
MC5R
MC1R
_____ is dark, brown–black, and insoluble, whereas ______ is light, red–yellow sulfur-containing, and soluble
Eumelanin
pheomelanin
synthesis of both types of melanin involves the rate-limiting catalytic step in which the amino acid tyrosine is oxidized by the enzyme ______ to DOPA, a first step in a reaction known as the _______
tyrosinase
Raper–Mason pathway
Conversion of tyrosine to DOPA is thought to be the critical rate-limiting step in melanogenesis, as inhibition of this reaction blocks melanin synthesis
The main function of melanin is to provide _________________________ by absorbing and scattering UV radiation (280–400 nm)
protection against UV-induced DNA damage
______ are branching protoplasmic processes that interact with keratinocytes. ______ is a major structural component of melanocyte dendrites, and disruption leads to dendrite loss
Melanocyte dendrites
Actin
Melanosome transport takes place on microtubules that are arranged parallel to the long axis of the dendrite and is controlled by two classes of microtubule-associated motor proteins: ____ and _____
Both motor proteins act as short cross-bridge structures connecting the organelle to the microtubules
(1) kinesins and (2) cytoplasmic dyneins
Centrifugal, anterograde organelle movement is mediated primarily by kinesin, whereas centripetal movement is controlled by cytoplasmic dynein
For melanosomes with net centrifugal movement, the bidirectional movement appears to terminate with ________ in the actin-rich periphery of the dendrite
myosin-Va (encoded by dilute locus)-dependent melanosomal capture
________ that mediates myosin-Va binding to melanosomes through another linker protein-melanophilin (encoded by leaden locus)
Rab27a (encoded by ashen locus)
______, a rare autosomal recessive disorder in which individuals display dilute skin and hair color, is the result of mutations of myosin-Va, Rab27a, or melanophilin. Myosin-Va and Rab27a are closely located on chromosome 15.
Griscelli syndrome
________—slender, filliform, pointed cytoplasmic projections at the tip of melanocyte dendrites.
These adhere and fuse with keratinocyte plasma membrane prior to melanosome transfer
filopodia
Another way of melanosomal transfer involves shedding of melanosome-filled vesicles followed by phagocytosis of these vesicles by keratinocytes, or their fusion with keratinocyte plasma membrane
Activation of _____ increases keratinocyte phagocytic activity.
Interestingly, and consistent with its role in melanosome phagocytosis, UV induces its activity and expression.
PAR-2
UV effect on PAR-2 activity and expression is more pronounced in individuals with skin phototypes II and III than in those with skin phototype I
_____ was also reported to enhance the repair of UV-induced DNA damage in melanocytes, specifically the repair of pyrimidine dimers, and also to reduce the level of UV-induced hydrogen peroxide in the cell
α-MSH
_____ appears to play a role in mature melanocytes, inducing melanogenesis by acti- vating tyrosinase and increasing TRP-1 levels.
It also leads to melanocyte proliferation and promotes dendrite formation
It displays photoprotective effects on melanocytes, enhancing thymine dimer repair, decreasing the level of UV-induced hydrogen peroxide, and inducing the level of antiapoptotic proteins
ET-1
_____ stimulates melanocyte dendrite formation and activates tyrosinase, and UV irradiation upregulates the level of PG receptors on melanocytes
PGF2α
leukotrienes B4 and C4 increase melanin synthesis and stimulate melanocyte proliferation and motility
Both neurotropins ___ and ____, the latter expressed by dermal fibroblasts, increase melanocyte survival
NGF and NT-3
____ binds tyrosine kinase transmembrane receptors to induce its mitogenic effect in the presence of cAMP elevating factors
Basic fibroblast growth factor (bFGF)
Keratinocyte growth factor, another member of the FGF family of proteins, has been shown to pro- mote melanosome transfer from melanocytes to keratinocytes
____ increases tyrosinase activity and melanogenesis and is thus an autocrine as well as paracrine molecule that affects melanocyte behavior in skin
NO
_____ bind either α1-adrenergic receptors (AR) or β2-AR and can induce melanogenesis through PKC-β or cAMP-dependent pathways
catecholamines
______ were shown to decrease melanogenesis, at least in part by enhancing MITF degradation via ubiquitin-meditated pathways
Sphingolipids
_____, downregulates tyrosinase expression in melanocytes, also in part via its effects on MITF
BMP-4
critical role of PKC in melanogenesis was first suggested by the observation that addition of ____, the endogenous activator of PKC, to cultured human melanocytes rapidly increased total melanin content, and this increase was blocked by a PKC inhibitor
DAG
Human melanocytes express PKC-α, -β, -ε, -δ, and -ς, and the PKC-β isoform is specifically involved in regulating tyrosinase activity
_____ interacts with melanocyte derived-norepinephrine and increases the level of DAG inducing melanogenesis in a PKC- β-dependent pathway
α1-AR
keratinocytes produce epinephrine, which then binds to____ expressed on
melanocytes and increases the level of cAMP, leading to melanin synthesis
β2-AR
___________ occurs within 5–10 minutes of exposure and fades within minutes to days depending on the UV dose and the complexion of the individual
Immediate tanning or immediate pigment darkening
represent melanosomal relocation from the perikaryon to melanocyte dendrites
primarily produced by UVA irradiation, although visible light can also induce immediate tanning
_____ occurs within 3–4 days after UV exposure
Delayed tanning
affected by both UVB and UVA
peaks between 10 days and 3–4 weeks depending on the absorbed UV dose and the individual’s skin type, then fades gradually over a few weeks
Most _____ are assumed to be the result of oxidative damage mediated through its absorption by cellular chromophores like melanin precursors that act as photosensitizers leading to the generation of ROS and free radicals
UVA effects
_____ irradiation is directly absorbed by cellular DNA, leading to the formation of DNA lesions, mainly cyclobutane dimers and pyrimidine (6–4) pyrimidone photoproducts
UVB
UV-induced melanogenesis can be augmented in pigment cells by treatment with _______, an enzyme that acts exclusively to enhance the repair of UV-induced DNA damage
T4 endonuclease V
____, a tumor-suppressor protein and transcription factor termed the Guardian of the Genome, when activated, upregulates the level of tyrosinase mRNA and protein, enhancing melanogenesis
p53
p53 activation stimulates POMC transcription, thereby increasing the release of POMC-derived α-MSH, a key physiologic inducer of melanogenesis
p53 transcriptionally upregulates the hepatocyte nuclear factor-1α (HNF- 1α) that is a transcription factor for tyrosinase
__ is known to increase H2O2 that activates p53.
UV
With aging, there is a decrease in the density of epidermal melanocytes (number per unit area of skin surface), approximately __% per decade
10%
total loss of melanocytes in approximately half of all scalp follicles by _____
middle age
