Chapter 72 Biology of Melanocytes

Question 1

_____ are pigment-producing cells that originate from the dorsal portions of the closing neural tube in vertebrate embryos

Answer 1

Melanocytes

derive from pluripotent neural crest cells that differentiate into numerous cell lineages including neurons, glia, smooth muscle, craniofacial bone, cartilage, and melanocytes

Question 2

Melanocyte stem cells reside in the______

Answer 2

hair follicle bulge

Question 3

There is approximately one melanocyte per _______

Answer 3

five or six basal keratinocytes

Question 4

Melanocytes synthesize ______, a pigmented polymer that is stored in cytosolic organelles called ______ that are transferred to keratinocytes through melanocyte dendritic processes

Answer 4

melanin

melanosomes

Question 5

The term _______ describes a single epidermal melanocyte surrounded by several epidermal keratinocytes

Answer 5

epidermal melanin unit

Question 6

Melanocyte density/mm2 ranges from approximately 550 to >1,200 with the highest concentrations found in the _______

Answer 6

genitalia and face

Question 7

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

Answer 7

proximal hair bulb

Question 8

______ are large (∼0.9 × 0.3 μm), elliptical in shape and contain a highly structured fibrillar glycoprotein matrix required for _____ synthesis

Answer 8

Eumelanosomes

eumelanin

Question 9

______ are smaller (∼0.7 μm in diameter), spherical in shape and their glycoprotein matrix appears disorganized and loose

Answer 9

Pheomelanosomes

Question 10

_______ gene maps to chromosome 11. The human tyrosinase gene is composed of five exons and four introns

Answer 10

human tyrosinase

Question 11

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 _______

Answer 11

ER
Golgi complex
glycosylation

Question 12

_____ residues present in the inner (catalytic) portion of tyrosinase bind _____ and the latter are required for tyrosinase activity

Answer 12

Histidine

copper (Cu) ions

Question 13

______ must phosphorylate two serine residues on this cytoplasmic domain to activate tyrosinase, and in the absence of those phosphorylation events pigmentation does not occur

Answer 13

protein kinase C-β (PKC-β)

Question 14

Tyrosinase mutations including missense, nonsense frameshift, and deletion mutations that lead to inactivation of the enzyme are found in _______

Answer 14

oculocutaneous albinism type I

Question 15

in human melanocytes, the _______ complex translocates to the melanosome membrane to allow tyrosinase phosphorylation

Answer 15

activated PKC-β/RACK-I

Question 16

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.

Answer 16

Pmel17

Melanosomes lacking Pmel17 cannot transit to stage II and have no active melanogenesis

Question 17

________, is a membrane-associated protein that is present in stage I and stage II melanosomes and forms a complex with Pmel17

Answer 17

MART-1, also known as Melan A

Question 18

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

Answer 18

Hermansky–Pudlak syndrome
AP-3 adaptor protein complex

AP-3 and possibly also AP-1 facilitate tyrosinase transport from endosomes to melanosomes

Question 19

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

Answer 19

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

Question 20

scavengers of free radicals that are produced during melanin biosynthesis

Answer 20

Lysosome-Associated Membrane Proteins

Question 21

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.

Answer 21

Microphthalmia-Associated
Transcription Factor

In melanocytes, it is the MITF-M isoform that stimulates transcription of tyrosinase and PKC-b.

Question 22

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

Answer 22

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.

Question 23

expression of MITF is under the control of several transcription factors, including Sox10 (mutated in ______) and Pax3.

Answer 23

Waardenburg’s syndrome type 4

Question 24

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 _______

Answer 24

BCl2
melanomas
Waardenburg syndrome type 2

Question 25

____ 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

Answer 25

MC3R and MC4R
MC2R
MC5R
MC1R

Question 26

_____ is dark, brown–black, and insoluble, whereas ______ is light, red–yellow sulfur-containing, and soluble

Answer 26

Eumelanin

pheomelanin

Question 27

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 _______

Answer 27

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

Question 28

The main function of melanin is to provide _________________________ by absorbing and scattering UV radiation (280–400 nm)

Answer 28

protection against UV-induced DNA damage

Question 29

______ are branching protoplasmic processes that interact with keratinocytes. ______ is a major structural component of melanocyte dendrites, and disruption leads to dendrite loss

Answer 29

Melanocyte dendrites

Actin

Question 30

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

Answer 30

(1) kinesins and (2) cytoplasmic dyneins

Centrifugal, anterograde organelle movement is mediated primarily by kinesin, whereas centripetal movement is controlled by cytoplasmic dynein

Question 31

For melanosomes with net centrifugal movement, the bidirectional movement appears to terminate with ________ in the actin-rich periphery of the dendrite

Answer 31

myosin-Va (encoded by dilute locus)-dependent melanosomal capture

Question 32

________ that mediates myosin-Va binding to melanosomes through another linker protein-melanophilin (encoded by leaden locus)

Answer 32

Rab27a (encoded by ashen locus)

Question 33

______, 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.

Answer 33

Griscelli syndrome

Question 34

________—slender, filliform, pointed cytoplasmic projections at the tip of melanocyte dendrites.
These adhere and fuse with keratinocyte plasma membrane prior to melanosome transfer

Answer 34

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

Question 35

Activation of _____ increases keratinocyte phagocytic activity.
Interestingly, and consistent with its role in melanosome phagocytosis, UV induces its activity and expression.

Answer 35

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

Question 36

_____ 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

Answer 36

α-MSH

Question 37

_____ 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

Answer 37

ET-1

Question 38

_____ stimulates melanocyte dendrite formation and activates tyrosinase, and UV irradiation upregulates the level of PG receptors on melanocytes

Answer 38

PGF2α

leukotrienes B4 and C4 increase melanin synthesis and stimulate melanocyte proliferation and motility

Question 39

Both neurotropins ___ and ____, the latter expressed by dermal fibroblasts, increase melanocyte survival

Answer 39

NGF and NT-3

Question 40

____ binds tyrosine kinase transmembrane receptors to induce its mitogenic effect in the presence of cAMP elevating factors

Answer 40

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

Question 41

____ increases tyrosinase activity and melanogenesis and is thus an autocrine as well as paracrine molecule that affects melanocyte behavior in skin

Answer 41

NO

Question 42

_____ bind either α1-adrenergic receptors (AR) or β2-AR and can induce melanogenesis through PKC-β or cAMP-dependent pathways

Answer 42

catecholamines

Question 43

______ were shown to decrease melanogenesis, at least in part by enhancing MITF degradation via ubiquitin-meditated pathways

Answer 43

Sphingolipids

Question 44

_____, downregulates tyrosinase expression in melanocytes, also in part via its effects on MITF

Answer 44

BMP-4

Question 45

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

Answer 45

DAG

Human melanocytes express PKC-α, -β, -ε, -δ, and -ς, and the PKC-β isoform is specifically involved in regulating tyrosinase activity

Question 46

_____ interacts with melanocyte derived-norepinephrine and increases the level of DAG inducing melanogenesis in a PKC- β-dependent pathway

Answer 46

α1-AR

Question 47

keratinocytes produce epinephrine, which then binds to____ expressed on
melanocytes and increases the level of cAMP, leading to melanin synthesis

Answer 47

β2-AR

Question 48

___________ occurs within 5–10 minutes of exposure and fades within minutes to days depending on the UV dose and the complexion of the individual

Answer 48

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

Question 49

_____ occurs within 3–4 days after UV exposure

Answer 49

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

Question 50

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

Answer 50

UVA effects

Question 51

_____ irradiation is directly absorbed by cellular DNA, leading to the formation of DNA lesions, mainly cyclobutane dimers and pyrimidine (6–4) pyrimidone photoproducts

Answer 51

UVB

Question 52

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

Answer 52

T4 endonuclease V

Question 53

____, 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

Answer 53

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

Question 54

__ is known to increase H2O2 that activates p53.

Answer 54

UV

Question 55

With aging, there is a decrease in the density of epidermal melanocytes (number per unit area of skin surface), approximately __% per decade

Answer 55

10%

Question 56

total loss of melanocytes in approximately half of all scalp follicles by _____

Answer 56

middle age