Regulation of Blood–Testis Barrier (BTB) Dynamics during Spermatogenesis via the “Yin” and “Yang” Effects of Mammalian Target of Rapamycin Complex 1 (mTORC1) and mTORC2 - International Review of Cell and Molecular Biology - page 323

reported that after fasting that caused loses in weight and protein content
in liver, the liver mass and total protein content of both wild-type and rpS6
conditional knockout mice recovered to the same extent and at the same
rate, clearly demonstrating rpS6 is dispensable for cell growth and protein
synthesis ( Volarevic et al., 2000 ). Furthermore, in liver, relative proportion
of ribosomes associated with polysomes was similar between rpS6 p−/− and
wild-type mice ( Ruvinsky et al., 2005 ). More importantly, in mouse embry-
onic fibroblasts (MEFs) that derived from rpS6 p−/− mice, instead of protein
synthesis retardation, a significant increase in rate of protein synthesis was
observed ( Ruvinsky et al., 2005 ). The studies using rpS6 p−/− mice revealed
that phosphorylation of rpS6 was not necessary for the efficient polysome
recruitment for translation, and in fact protein synthesis was negatively regu-
lated by phosphorylated rpS6. Therefore, it is now generally accepted that
upon stimulations, such as by growth factors, mitogens and nutrients, that
induce cell growth, mTORC1 upregulates protein synthesis via its substrates,
S6K and 4E-BP1. The role of rpS6 is likely to fine tune the above process by
playing a role as a negative regulator ( Ruvinsky and Meyuhas, 2006 ). Similar
to the kinase S6K, rpS6 may also be involved in the regulation of cell prolif-
eration, such as proliferation of liver cells ( Volarevic et al., 2000 ). Also, mouse
embryonic fibroblasts derived from rpS6 p−/− displayed an accelerated cell
division, indicating rpS6 phosphorylation regulates cell proliferation nega-
tively in these fibroblasts ( Ruvinsky et al., 2005 ).
3.2.2.3. 4E-Binding Protein 1
Besides S6K, another well-characterized substrate of mTORC1 for medi-
ating protein synthesis is 4E-BP1, which is a repressor of the translation
initiation factor eIF4E ( Pause et al., 1994 ). When mTORC1 signaling is not
activated, eIF4E is sequestered by hypophosphorylated 4E-BP1. However,
upon stimulation such as growth factors and mitogens, activated mTORC1
phosphorylates 4E-BP1 at six sites: T37, T46, T70, S65, S83 and S112, lead-
ing to dissociation of 4E-BP1 from eIF4E. eIF4E is thus free to bind to
eIF4G, which is a scaffolding protein that recruits eIF4A and coordinates
the binding of small ribosomal subunits to the mRNA. Association of eIF4E
with eIF4G and eIF4A forms a complex called eIF4F which binds to the
5′-end of mRNA ( Marcitrigiano et al., 1999 ) for the recruitment of 40S
ribosome and eventually results in the formation of 48S translation preini-
tiation complex ( Gingras et al., 1999 ).
Other than regulating cell growth and proliferation, mTORC1 signal-
ing plays a wide variety of physiological roles including autophagy, aging,