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kinases that has two members, namely S6K1 and S6K2, which are encoded by
two different genes and share high homology (
Lee-Fruman et al., 1999
). The
necessity of S6K in regulating cell and body size is well illustrated in genetic
models deficient in either S6K1 or S6K2, or both. The loss of function of S6K
in
Drosophila
led to a serve decline in body size due to reduction in cell size
rather than cell number (
Montagne et al., 1999
). In mice lacking S6K1, body
size was significantly smaller
versus
the wild type at birth and during postnatal
growth, attributing by the reduced size in all organs (
Shima et al., 1998
). The
reduction in size of organs was probably caused by decreased cell size, such
as pancreatic β-cells (
Pende et al., 2000
) and myoblasts (
Ohanna et al., 2005
).
In contrast, in mice lacking S6K2, body size was insignificantly different from
the wild type at birth and during postnatal development, suggesting S6K2 is
not required for regulating cell size in rodents. Furthermore, in mice deficient
in both S6K1 and S6K2, body size of the surviving animals during embryonic
and postnatal growth was not further reduced compared to that of S6K1-
deficient mice (
Pende et al., 2004
) and the size of myoblasts from S6K1- and
S6K2-deficient mice was similar to that of mice lacking S6K1 (
Pende et al.,
2004
). These findings thus suggest that control of cell size seems to be mostly
regulated by S6K1 in rodents. Moreover, it has been reported that mice lack-
ing both forms of S6K are prone to suffer perinatal death, unlike mice lacking
either form of S6K, which were viable and fertile (
Pende et al., 2004
). This
indicates that although S6K2 may not contribute as much as S6K1 in regulat-
ing cell size, these two isoforms do have overlapping roles and therefore, loss
of one isoform can be superseded, at least in part, by the other.
Ribosomal protein S6 (rpS6) was the first identified substrate of S6K1 for
modulating protein synthesis (
Gressner and Wool, 1974
). Subsequent studies
have identified other substrates of S6K1, which include elongation factor 2
(EF2) kinase, eukaryotic initiation factor 4B (eIF4B), programmed cell death 4
(PDCD4) and S6K Aly/REF-like substrate (SKAR) that promote protein syn-
thesis via up-regulating translational activity. It is known that S6K1 phosphor-
ylates and inactivates EF2 kinase (EF2K), leading to dephosphorylation and
activation of EF2, which in turn promotes translation elongation (
Wang et al.,
2001
). S6K1 also phosphorylates eIF4B on S422, resulting in enhanced trans-
lation initiation by stimulating the RNA helicase eIF4A to unwind mRNA
for translation (
Raught et al., 2004
). The above process is further enhanced by
phosphorylating the eIF4A inhibitor, PDCD4 (note: each PDCD4 molecule
can bind two molecules of eIF4A) by S6K1 on S67 as such phosphorylation
promotes PDCD4 degradation (
Dorrello et al., 2006
;
Shahbazian et al., 2006
).
Furthermore, studies revealed that S6K1 also promoted protein translation by
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