Schematic
representation of proposed intracellular effects of S100B. S100B
interacts with several intracellular proteins as shown thereby
regulating protein phosphorylation, enzyme activities, the state of
assembly of certain cytoskeleton components, the transcription factor
p53, protein degradation, cell proliferation, locomotion and
differentiation, dark adaptation of photoreceptors, Ca2+ homeostasis and the innate inflammatory response.
S100B is
expressed in
astrocytes,
certain neuronal populations, Schwann cells,
melanocytes, chondrocytes, adipocytes, skeletal myofibers and associated
satellite cells,
certain dendritic cell and lymphocyte populations and a
few other cell types [
7]. It acts as a stimulator of cell proliferation and migration and an inhibitor of apoptosis and differentiation [
101-
111] (),
which might have important implications during
brain, cartilage and
skeletal muscle d
evelopment and
regeneration/repair,
activation of
astrocytes in the course of brain damage and
neurodegenerative
processes, and of cardiomyocyte remodeling after infarction, as well as
in melanomagenesis and
gliomagenesis. In particular,
downregulation of
S100B expression in precursor cells in a defined temporal window appears
to be
permissive for cell differentiation [
101-
106,
108-
110].
Sex-determining region Y-type high mobility group box 5, 6 and 9 (the
so-called SOX trio), NF-κB, EGF and the Th-1-derived cytokine IFN-γ,
regulate S100B expression in several cell types [see
7 for review; also see
12].
However, cells that downregulate S100B expression at the onset of their
differentiation resume S100B expression at completion of development [
7,
106],
and in mature cells the protein regulate a large variety of key
activities including
maintenance of shape, transcription, protein
degradation,
Ca2+ homeostasis, energy metabolism and enzyme
functions by interacting with a wide array of target proteins. Binding
partners of S100B within cells are
tubulin and
the
microtubule-associated τ protein, the actin-binding protein caldesmon,
calponin, type III intermediate filament subunits, annexin 6 [
7,
112-
119],
membrane-bound guanylate cyclase, the small GTPase Rac1 and Cdc42
effector IQGAP1, Src kinase, the serine/threonine protein kinase Ndr,
the tumor suppressor p53, intermediates upstream of IKKβ/NF-κB, the
giant phosphoprotein AHNAK/desmoyokin, the
E3 ligase hdm2,
dopamine D2
receptor and the mitochondrial AAA ATPase, ATAD3A [
7,
120,
121] ().
Thus, lack of S100B downregulation may maintain cell proliferation with
potential beneficial effects during development and tissue
regeneration, and detrimental effects during tumorigenesis. S100B also
regulates Ca
2+ homeostasis [
122-
125], but opposing results were reported in astrocytes and VSMCs [
122,
124] (). Moreover, S100B binds to, and inhibits EAG1 potassium channels Ca
2+-dependently () raising the possibility that its negative effects on cell differentiation may be
via this mechanism as well [
125].
Chronically high S100B levels such as those obtained in S100B
transgenic mice are proposed to be causally correlated with Parkinson's
disease likely
via downregulation of dopamine D2 receptor and G
protein-coupled receptor kinase2 expression, increased dopamine
synthesis and metabolism, and decreased serotonin levels [
126]
and/or S100B interaction with the third cytoplasmic loop of the
dopamine D2 receptor and extracellular signal-regulated kinase
(ERK)1/2-mediated inhibition of adenylyl cyclase activity in striatal
neurons [
127] ().
S100B is highly expressed in astrocytes [
7] and to a lesser extent in certain neuronal populations [
128,
129], and
its elevation in serum positively correlates with mood disorders [130] and schizophrenia [
131]. Serum levels of S100B are of prognostic value in patients with cutaneous melanoma [
105] and breast cancer [
132].
Whether serum levels of S100B are an outcome predictor in severe traumatic brain injury is a matter of debate [
133,
134].
