Aveneu Park, Starling, Australia

P62/Sequestosome1 autophagic degradation of proteins42 and in signal transduction43-44.

P62/Sequestosome1
(SQSTM1) is a multifunctional cytoplasmic protein involved in multiple cellular
functions; the protein plays role in autophagic degradation of proteins42 and in signal transduction43-44. Along with variety of environmental and
genetic factors responsible for impaired metabolic homeostasis leading to aging,
p62 is also known to be involved in age-related metabolic dysfunction such as obesity
and type 2 diabetes. It is evidenced that in physiological conditions
extracellular signal-regulated kinase 1 (ERK1) signalling is dampened by
p62/SQSTM1, which sequesters the kinase into p62 bodies through its PB1 domain
(Figure 3); thus preventing excessive differentiation and proliferation of
white adipocytes45. This indicates that loss of p62/SQSTM1 with
age contributes to the increased fat accumulation and metabolic disorders seen
in the elderly. Brown fat is progressively lost with age, and higher amount of
brown fat have been negatively correlated with insulin resistance and obesity46-47. Moreover, it has been shown that p62/SQSTM1
may favour the acquisition of brown fat features by promoting beta-oxidation
through Peroxisome proliferator-activated receptor-gamma coactivator
(PGC)-1alpha, Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), and Nuclear
respiratory factor 1 (NRF1) transcription factors involved in the expression of
genes for lipid metabolism48-50. Hence, it is possible that loss of p62/SQSTM1
expression may contribute to age-related loss of brown fat and consequently to
the onset of age-related metabolic dysfunctions such as diabetes. Furthermore,
aging correlates also with decreased production of insulin51; insulin is released by the pancreatic
beta-islets in response to glucose availability. Interestingly, beta-islets
from type 2 diabetes patients show mitochondrial dysfunction, which leads to
reduced insulin release52 and impaired ATP production. Considering the
vital role p62/SQSTM1 plays in maintaining the mitochondrial homeostasis53-54, it is likely that age-related loss of
p62/SQSTM1 in beta-cells could contribute to this mitochondrial dysfunction,
thus leading to reduced insulin release, which may result in diabetic
conditions. In addition to p62/SQSTM1 role in diabetes, there are ample
evidences of its involvement in breast cancer. A study conducted on 163 Triple
Negative Breast Cancer (TNBC) patients suggested that high levels of p62 were
associated with high biological aggressiveness of TNBC cells, because higher
risk of distant metastases was exhibited by patients with p62 overexpression55; in the study, p62-negative was a significant
independent prognostic factor of disease-free survival (P=0.017), but not for
overall survival (P=0.845) in all patients. In another study, aberrant p62
overexpression implication was observed in breast cancer development, where p62
expression was found elevated in Breast Cancer Stem Cells (BCSCs) including
CD44+CD24- fractions, mammospheres, ALDH1+
populations and side population cells56. Further, it was revealed in the study by gene
expression profiling analysis that p62 was positively correlated with MYC mRNA
expression level, which mediated the function of p62 in promoting breast cancer
stem-like properties; upon deletion of p62 by siRNA the level MYC mRNA was
reduced, whereas, the level was increased with p62 overexpression, suggesting
the role of p62 in positively regulating MYC mRNA. Hence, together these
findings of association of p62/SQSTM1 in diabetes and breast cancer unveil an
unappreciated role of p62 in these diseases regulations, which makes p62 a
promising therapeutic target. With our approach in this project, we strive to
reveal the importance of p62 by studying relevant drug targets and their
binding affinities with p62 using our computational methods. This way we will
investigate and provide answers to questions left untouched by experimental
approaches.

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