The expected lifespan of Pakistani population according to a survey carried out by World Bank is expectancy in Pakistan is 65.7 years for males and 67.4 years for females, with an average of 66.5 years.1 Longevity is a multifactorial trait and various genes are thought to play an important role among which FOXO gene is of particular significance.2 FOXO proteins are a member of the Fork head Family of transcription factors which are common integration point for many important cellular processes.3 Four mammalian FOXOs - FOXO1, FOXO3, FOXO4
and FOXO6 have been documented in mammals.3 FOXO3, a key regulator in insulin/IGF-1 signaling pathway (IIS), is known to have a protective role against biological and environmental stress factors thereby resulting in longer lifespan.4
(20) Instead, the transcription factors nuclear transcription factor Y (NF-Y), forkhead box protein O4 (FOXO4
), and signal transducer and activator of transcription 3 (STAT3) were identified as regulators of constitutive proteasome expression.
In FoxO1-deficient mouse models, embryonic lethality occurs with incomplete embryogenesis, whereas mice lacking either FoxO3 or FoxO4
survive even after parturition .
In addition, inactivation of FOXO1, FOXO3, and FOXO4
(or FOXO3 only ) results in defective self-renewal and differentiation of NSCs, paralleled by increased ROS production .
In this context, the first analysis of PTEN/PI3K/AKT/mTOR pathway activation in patient specimens was carried out on 45 untreated primary GBM; immunohistochemistry analysis revealed that PTEN loss correlated with AKT activation and that in turn AKT phosphorylation significantly correlated with mTOR, FOXO1, FOXO3a, FOXO4
, and S6 activation .
The peptide stops levels of a protein called FOXO4
from increasing in senescent cells - those that remain metabolically active, but lose their ability to replicate and destroy themselves.
Yannan and Haihang conducted microarray analysis on two CRC cell lines with drastically different metastatic capabilities and found miRNA-499-5p to play a pivotal role in tumor metastasis by targeting forkhead box protein O4 (FOXO4
) and programmed cell death 4 (PDCD4) .
Activated Akt also phosphorylates FoxO proteins (FoxO1, FoxO3, and FoxO4
), inhibiting their action by promoting their nuclear exclusion and degradation.
In this regard, the transcription factors FoxO1, FoxO3a, and FoxO4
are critical mediators of the cellular responses to oxidative stress and have been implicated in many of ROS-regulated processes .
PCR primers of FOXO4
gene were designed by the Primer 3 software (http://bioinfo.ut.ee/ primer3-0.4.0/primer3/).
The expression levels of Akt and GSK-3[beta], the phosphorylation of FoxO4
, and the phosphorylations of AMPK and mitochondrial-related transcription factors such as PGC-1[alpha] were suppressed, while the expression of MuRF1 increased in SAMP8 mice, but approximated that in senescence-accelerated aging-resistant (SAMR1) mice after GJG treatment.
The top 10 ranked TFs with higher RIF were HAND1, PTK1, NFKB1, ZIC3, STAT6, E2F1, PELP1, USF2, CBFB, SOX9, and FOXO4