Biomedical Engineering Reference
In-Depth Information
Emerging roles for ARFRP1 have been described in the formation of lipid
droplets (adipocytes) and chylomicrons (enterocytes) (Hesse et al.
2013
). Lipid
droplets are dynamic organelles that store neutral lipids and are involved in the
regulation of lipid metabolism (Martin and Parton
2006
). Adipocyte-specific
knockout of ARFRP1 in mice resulted in loss of triglyceride storage, decreased
lipid droplet size, and increased lipolysis (Hommel et al.
2010
). Chylomicrons are
lipid-carrying organelles in intestinal cells that transport dietary fat and fat-soluble
vitamins to the bloodstream via the lymphatic system (Xiao and Lewis
2012
).
Enterocyte-specific knockout of ARFRP1 resulted in reduced triglyceride content
of chylomicrons and decreased association of lipoproteins, such as apolipoprotein
A-I (Jaschke et al.
2012
). Through regulating the maturation and lipidation of lipid
droplets and chylomicrons, ARFRP1 is essential for the proper regulation of lipid
traffic and metabolism.
10.4 ARL2
ARL2 is ubiquitously expressed and highly conserved throughout eukaryotic evo-
lution. It is an ancient protein dating back to the last eukaryotic common ancestor
(Li et al.
2004
; Logsdon and Kahn
2004
) and is essential in all model organisms
where it has been studied [including
S. pombe, A. thaliana,
and
C. elegans
(Hoyt
et al.
1990
; McElver et al.
2000
; Radcliffe et al.
2000
; Antoshechkin and Han
2002
)], with the exception of
S. cerevisiae
(
CIN4
; (Hoyt et al.
1990
; Stearns
et al.
1990
). It has arguably become the most studied ARL to date, both because
it is essential and because it has been implicated in a variety of human diseases,
including cancer, heart disease, and retinal degeneration (Mori et al.
2006
; van
Rooij et al.
2006
; Beghin et al.
2008
,
2009
; Nishi et al.
2010
). ARL2 acts in at least
four different locations within cells: cytosol, mitochondria, centrosomes, and
nuclei. No ARL2 GEFs have been described to date and its distinctive
nucleotide-binding properties, at least within the ARF family, and tight binding
to the tubulin-specific co-chaperone, cofactor D, suggest either that it does not use a
GEF or that the mechanism of activation will be different from other members of
the ARF family.
ARL2 appears to be capable of functioning as a tumor suppressor with poten-
tially important clinical relevance for chemotherapy. Levels of ARL2 expression in
breast cancer cells are directly linked to three-dimensional growth in vitro and
tumor growth in vivo. Stable knockdown of ARL2 in MCF-7 cells increased tumor
size compared to control MCF-7 cells when injected into adult mammary fat pads
of immunodeficient (SCID) mice. Conversely, stable upregulation of ARL2 expres-
sion decreased tumor size. The ARL2 expression level was also correlated with
sensitivity of MCF-7 cells to several different chemotherapeutics, including taxol,
gemcitabine, and doxorubicin (Beghin et al.
2008
), with higher levels of ARL2
resulting in greater sensitivity to these agents. There was also a correlation between
ARL2 protein levels in primary tumors with tumor size and metastasis in human
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