October 7, 2011

New Cellular Malfunctions in Cancer

(Ivanhoe Newswire) -- Malfunctioning machines can cause a slew of problems, but when those machines are cells and genes, the result is often cancer.  Scientists have identified a new protein that is crucial to the cell's response to dietary amino acids.

One particular piece of cellular machinery known to malfunction in a number of cancers is a group of proteins called mTORC1. This group is like a master control center coordinating many cellular functions by sensing external signals, such as nutrients and growth factors, and telling cells how to respond.

Scientists at Stanford-Burnham Medical Research Institute have identified a new member of the mTORC1 team, a protein called p62.

"In this study, we looked for new p62 binding partners and found that p62 interacts with components of the well known mTORC1 complex," Maria Diaz-Meco, Ph.D., professor in Stanford-Burnham's NCI-designated Cancer Center and senior author of the study was quoted as saying.

The finding provides new information about mTORC1 and its role in cellular metabolism in both normal and cancer cells. It also gives scientists a new therapeutic target for cancers in which mTORC1 malfunctions.

"We think of p62 as a signaling hub - it has several domains that can bind many different proteins to regulate important cellular function like growth and survival. Levels of p62 are also elevated in many cancers," Dr. Diaz-Meco was quoted as saying.

The amino acids a person consumes set off a chain reaction that involves mTORC1, but only some of the players in this string of events are fully understood. The study fills in some of the gaps by showing that amino acids trigger p62 to bind to a protein called raptor. P62 and raptor then join mTORC1, activating the complex.

"Now we want to fill in more blanks until every step in this pathway is completely understood. This information will allow us to better understand cellular metabolism and its link to human diseases such as cancer," Diaz-Meco was quoted as saying.

One common way of determining a protein's function is to see what happens in cells that don't have it. When the team generated mice and cells that lack p62, they saw that mTORC1 no longer responded to amino acids. In other words, p62 is required for mTORC1 activation by amino acids, and only amino acid stimulation required p62.

"The study helps connect the dots between amino acids in the diet and downstream cellular processes like protein synthesis and cellular growth. It also shows us just how important cellular location is in the mTORC1 pathway - if the complex isn't located in the lysosome, it doesn't get activated," Dr. Diaz-Meco was quoted as saying.

Additional projects underway are aimed at pharmacologically targeting p62 and related proteins to generate new medicines for diseases such as cancer, type 2 diabetes, and obesity.

SOURCE: Molecular Cell, published October 7, 2011