Biology Reference
In-Depth Information
ecdysone titer. This developmental autophagy is induced during the wan-
dering larval stage and metamorphosis at times when the animal is not feed-
ing, suggesting that autophagy may play an important role in survival and
even tissue growth during nonfeeding periods (
Lee & Baehrecke, 2001;
Lee, Cooksey, & Baehrecke, 2002; Rusten et al., 2004
). In the fat body,
programmed autophagy is induced in response to ecdysone late during
the third larval stage. This induction requires the downregulation of class
I PI3K signaling (
Rusten et al., 2004
), suggesting that regulation of the class
I PI3K pathway is involved in both starvation-induced autophagy and de-
velopmental autophagy.
Studies in the
Drosophila
fat body have identified other genes that are
necessary for autophagy induced in response to ecdysone. SNF4A
g
, the
Drosophila
homologue of the AMP-activated protein kinase (AMPK)
g
sub-
unit, was identified in a fat body screen for mutants that fail to induce
autophagy in response to ecdysone (
Lippai et al., 2008
). AMPK is an evo-
lutionarily conserved enzyme that maintains cellular energy balance and is an
inhibitor of TOR signaling (
Shaw, 2009
). In mammalian cells, AMPK has
been implicated in the induction of autophagy in response to stimuli other
than starvation, including growth factor withdrawal and increased calcium
signaling (
Hoyer-Hansen et al., 2007; Liang et al., 2007
). Importantly,
several recent studies in mammalian cells have shown that AMPK may di-
rectly control ULK1, the mammalian homologue of Atg1, via phosphory-
lation; however, the exact sites of phosphorylation are still debated (
Egan
et al., 2011; Kim, Kundu, Viollet, & Guan, 2011; Lee, Park, Takahashi,
& Wang, 2010; Shang et al., 2011
). AMPK has also been shown to suppress
cell proliferation in
Drosophila
(
Mandal, Guptan, Owusu-Ansah, &
Banerjee, 2005
). Taken together, these studies suggest that AMPK is an im-
portant regulator of the relationship between autophagy and growth.
Studies in
Drosophila
have further investigated the relationship between
autophagy and growth. TOR is a key regulator of cell growth that was first im-
plicated in the regulation of autophagywhen rapamycin, a TOR inhibitor, was
shown to induce autophagy (
Blommaart, Luiken, Blommaart, vanWoerkom,
&Meijer, 1995
). TOR represses autophagy through phosphorylation of Atg1
(
Kamada et al., 2000; Scott, Juh´sz, & Neufeld, 2007
). In
Drosophila
larval fat
body, overexpression of Atg1 inhibits cell growth through a negative feedback
mechanism on TOR. Conversely,
Atg1
mutant cells with reduced TOR sig-
naling have increased growth (
Scott et al., 2007
). These results suggest that
autophagy is a negative regulator of cell growth. Interestingly, it has been shown
that inhibiting autophagy in a
TOR
null background enhances the
TOR
