Researchers find a protein that controls cell growth

Protein offers possibility of finding new cancer therapies

Researchers at New York University School of Medicine have found that a protein called APC plays a role in controlling a web of molecular interactions that can transform normal cells into cancerous ones. The finding may provide new possibilities for devising cancer therapies that target this protein.

“A tumor cell lacks the ability to limit its own growth,” says Michele Pagano, M.D., Associate Professor of Pathology, who led the new study published in the March 11 issue of Nature. “APC puts the brake on cell growth.”

The study sheds light on the relationship between APC and two other proteins involved in the development of cancer — Skp2 and p27. APC controls the abundance of Skp2, according to the study. Skp2 determines whether a cell will begin the process of making copies of itself, and it was previously tied to p27.

“This is a very important and exciting study,” says Avram Hershko, M.D., Ph.D., Distinguished Professor at Technion-Israel Institute of Technology in Haifa, who has made seminal contributions to understanding protein degradation and the cell cycle, the sequence of events a cell undergoes to make a copy of itself by dividing into two.

“Only recently has it been realized that Skp2 is a very important oncogene,” Dr. Hershko explained in an e-mail. “Dr. Pagano’s new study reveals how Skp2 itself is eliminated. This knowledge may be used in the future to down-regulate (decrease the activity of) Skp2 in cancers, and thus to arrest the growth of these cancers.”

The gene encoding the p27 protein is one of about twenty so-called “tumors suppressor genes” that have been linked to cancer. When these genes aren’t fully activated or are mutated, cells lose their ability to limit their own growth. In previous studies, low levels of the p27 protein have been associated with the development of certain tumors of the breast, colon, lung, esophagus, bone marrow, and thymus. In a sense, APC indirectly controls the abundance of p27.

In 1997, Dr. Pagano’s group and other research teams separately reported that low levels of p27 correlated with a poor prognosis among patients with colorectal and breast cancers, regardless of tumor size. Since then, numerous reports have extended these original findings to many other types of tumors. In more recent studies, researchers have discovered that p27 and Skp2 were inversely correlated in certain tumors, so when Skp2 levels were high, p27 levels were low.

However, no one knew what controlled the cellular abundance of Skp2, which is now considered an oncogene. Alterations in oncogenes often lead to uncontrolled cell growth, and to cancer. Now, with this latest report in Nature, Dr. Pagano’s group has figured out that levels of Skp2 are controlled by APC; APC actually induces the degradation of Skp2.

Although this seeming alphabet soup of protein acronyms can be confusing to lay people, these proteins are of utmost interest to cancer researchers because they play an essential role in the cell cycle.

Disruptions in the breakdown of proteins associated with the cell cycle can lead to cancer, the uncontrolled growth of cells. In normal cells, Skp2 needs to be degraded in order for the cell to remain in a quiescent, or resting, state. When it isn’t degraded, its levels rise and then the cell is pushed into the initial stage of cell division, called the S phase, in which the cell synthesizes its DNA in preparation for replicating its genome.

In Dr. Pagano’s latest study, his group demonstrated that cells with high levels of a mutated form of Skp2 promoted the degradation of p27. As a result, these cells entered the S phase of the cell cycle faster than control cells with unmutated Skp2.

The premature entry of a cell into the S phase is a potential cause of genetic instability, which in turn can propel a cell into uncontrolled proliferation, resulting in cancer. Dr. Pagano says that his laboratory plans to ascertain whether there are mutations in the gene encoding the APC protein that cause Skp2 to accumulate. (If APC were mutated, then the instructions for Skp2 degradation would be missing). If so, then perhaps drugs can be developed that counter these mutations in APC.

“An increase in the amount of Skp2 contributes to cancer development,” says Dr. Pagano. “Since APC controls the cellular abundance of Skp2, we think that APC deregulation plays a role in the malignant transformation of cells. If we could find a way to decrease the levels of Skp2 or inhibit its activity — possibly through manipulation of APC — then we may be able to develop new cancer therapies.”

The Warren, New Jersey-based biotechnology company Celgene Corp. has given Dr. Pagano’s laboratory a grant to study the cellular function of some Skp2 homologs, which have similar sequences of amino acids, with the idea that this will lead to the identification of novel targets for cancer therapies. In addition, Dr. Pagano’s lab and Celgene are collaborating on a project to screen for inhibitors of Skp2, and several inhibitors already have been identified.

The co-authors of the Nature study are Tarig Bashir, Ph.D.; N. Valerio Dorrello, M.D.; Virginia Amador, Ph.D.; and Daniele Guardavaccaro, Ph.D. They are all members of Dr. Pagano’s laboratory.

The study was supported by numerous grants and fellowships, including two National Institute of Health grants to Dr. Pagano; a fellowship from the New York State Breast Cancer Research and Education fund to Dr. Bashir; a Human Frontiers Science Program fellowship to Dr. Amador; and an American-Italian Cancer Foundation fellowship and a Susan Komen Breast Cancer Foundation fellowship to Dr. Guardavaccaro.