Structural Biochemistry/p62

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General Information[edit]

PDB 2p62 EBI

P62 was initially discovered as a protein kinase C-interacting protein (PKC). P62 plays a versatile role in the body and maintains an important role in an abundance of cellular functions. An interesting characteristic of p62 is that it plays a major role in cell growth and cancer. P62 has the ability to modulate (and be a substrate of autophagy), warrant efficient mitosis of cells, and regulate ROS levels and limit misfolded proteins. All of these qualities of p62 play critical roles in the development of cancer, making p62 a primary regulator of tumorigenesis. [1]

Control of Cell Growth and Autophagy[edit]

Studies show that p62 plays a role in the activation of the mammalian target of rapamycin (mTOR) pathway, which is a key regulator of cell growth and autophagy. There are two multi-protein complexes of mTOR (mTORC1 and mTORC2). P62 primarily interacts with mTOR1 through a key component of mTORC1, raptor. mTORC1 senses several cellular/environmental signals including: protein misfolding, nutrient availability and growth signals. mTORC1 controls cell growth through the phosphorylation of S6K and 4EBP1, and regulates autophagy by targeting Ulk1 and Atg13. [1]

In cells with a deficiency in p62, the phosphorylation of S6K and 4EBP1 is diminished, therefore mTORC1 activity decreases and autophagy is increased. However, since p62 is a substrate of autophagy, mTORC1 activity is promoted. Under the conditions of nutrient deprivation, the interrelations between autophagy, p62, and mTORC1 can create a safeguard mechanism to ensure the irreversibility of cell death. [1]

Connecting the Pieces[edit]

Studies have also shown that the overexpression of p62 can lead to the generation of liver tumors. Consequently, it is important to regulate the accumulation of p62 in order to prevent tumorigenesis. P62 can accumulate with the inactivation of autophagy molecules (ex. Atg7) and lead to hepatotoxicity, thus promoting liver tumors. [1]

However, creating a model that links accurately links together autophagy and p62 to cancer is very complicated process with many contradictions. It would make sense to assume that autophagy would induce tumorigenesis in a nutrient deprived environment. But there is contradictory data that supports the contrary. An essential protein for autophagy is Beclin-1, which has been found to suppress tumor formation. Other tumor suppressors, such as phosphatase and tensin homolog and the TSC proteins, promote autophagy by inhibiting mTORC1. [1]

Overexpression of p62 has been linked to the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is a transcription factor that can suppress reactive oxygen species (ROS). Thus, one would come to the conclusion that reduced Atg7 deficiency (thus a decrease in autophagy), would lead to an accumulation of 62, which would lead to an increase in activation of NRF2, thus reducing oxidative stress. From this deduction, it would be sufficient to reason that the ablation of p62 in Atg7-deficient livers would make hepatotoxicity worse as there is a decrease in activated NRF2, which alleviates oxidative stress. However, studies have shown a stark contrast to this analysis. It has been shown that hepatotoxicity in Atg7-deficient mice is actually prevented by the inactivation of p62 instead of increased. This leads to an uncertainty in the relation between autophagy, p62, and tumorigenesis, and debunks the model previously proposed. [1]

Furthermore, the relationship between autophagy, p62, and cancer becomes more clouded by recent studies that show that Ras-induced transformation increases autophagy, but needs p62. However, amongst this puzzlement, this presents a detachment between p62 and autophagy; meaning that Ras-induced autophagy and Ras-induced p62 are independent of each other but both required for the Ras signal. For example, “Ras-induced autophagy would be required for the removal of damaged and dysfunctional mitochondria, which is thought to be associated with metabolic reprogramming and contributes to maintaining low ROS levels. Ras-induced p62 might shuttle the damaged mitochondria to the autophagosome by interacting with the autophagosomal membrane protein Atg/LC3.” [1]This shows that autophagy and p62 work in unison to control Ras mechanisms, but still maintain their own independence. [1]

Another transcription factor, known as NF-kB, is activated by Ras and the oligomerization of TRAF6 (caused by p62). Studies have shown a link between lung cancer and an overexpression of TRAF6. Therefore, inactivating TRAF6 will inactivate NF-kB and inhibit tumorigenesis. Though p62 can help regulate harmful levels of oxidative species, p62 can also promote tumorigenesis through the activation of NF-kB. From these observations, it is seen that p62 can affect tumorigenesis through two different transcription factors, NF-kB and NRF2. [1]

Remarks[edit]

It can be seen through the analysis of p62 knockout mice, that the central purpose of p62 under nonpathological conditions is to control bone and metabolic homeostasis. This function of p62 may lead to indirect control of cancer. Cancer metastasis is prevalent in bone and can be affected by crosstalk between tumor and bone cells. Thus, p62 has the possibility for being a therapeutic target in metastasis. Moreover, elevated amounts of p62 can help maintain metabolic homeostasis by decreasing adipogenesis. This can also lead to regulation of some forms of cancer, since it has been shown that obesity-induced inflammation and insulin resistance (results of adipogenesis) promote forms of cancer in both humans and mice. Similar to the protecting effects of elevated p62 (in regards to obesity), autophagy proteins in mice have been shown to also protect against obesity. [1]

References[edit]

  1. a b c d e f g h i j Moscat, Jorge, and Maria T. Diaz-Meco. "p62: a versatile multitasker takes on cancer." June 2012.