Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find a protein that controls cell growth

11.03.2004


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.

Pamela McDonnell | EurekAlert!
Further information:
http://www.med.nyu.edu/

More articles from Life Sciences:

nachricht Unravelling the genetics of fungal fratricide
16.10.2018 | Uppsala University

nachricht Fungal weapon turns against the maker
16.10.2018 | Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie - Hans-Knöll-Institut (HKI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Storage & Transport of highly volatile Gases made safer & cheaper by the use of “Kinetic Trapping"

Augsburg chemists present a new technology for compressing, storing and transporting highly volatile gases in porous frameworks/New prospects for gas-powered vehicles

Storage of highly volatile gases has always been a major technological challenge, not least for use in the automotive sector, for, for example, methane or...

Im Focus: Disrupting crystalline order to restore superfluidity

When we put water in a freezer, water molecules crystallize and form ice. This change from one phase of matter to another is called a phase transition. While this transition, and countless others that occur in nature, typically takes place at the same fixed conditions, such as the freezing point, one can ask how it can be influenced in a controlled way.

We are all familiar with such control of the freezing transition, as it is an essential ingredient in the art of making a sorbet or a slushy. To make a cold...

Im Focus: Micro energy harvesters for the Internet of Things

Fraunhofer IWS Dresden scientists print electronic layers with polymer ink

Thin organic layers provide machines and equipment with new functions. They enable, for example, tiny energy recuperators. In future, these will be installed...

Im Focus: Dynamik einzelner Proteine

Neue Messmethode erlaubt es Forschenden, die Bewegung von Molekülen lange und genau zu verfolgen

Das Zusammenspiel aus Struktur und Dynamik bestimmt die Funktion von Proteinen, den molekularen Werkzeugen der Zelle. Durch Fortschritte in der...

Im Focus: Dynamics of individual proteins

New measurement method allows researchers to precisely follow the movement of individual molecules over long periods of time

The function of proteins – the molecular tools of the cell – is governed by the interplay of their structure and dynamics. Advances in electron microscopy have...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Berlin5GWeek: Private industrial networks and temporary 5G connectivity islands

16.10.2018 | Event News

5th International Conference on Cellular Materials (CellMAT), Scientific Programme online

02.10.2018 | Event News

Major Project: The New Silk Road

01.10.2018 | Event News

 
Latest News

Unravelling the genetics of fungal fratricide

16.10.2018 | Life Sciences

Blue phosphorus -- mapped and measured for the first time

16.10.2018 | Physics and Astronomy

Berlin5GWeek: Private industrial networks and temporary 5G connectivity islands

16.10.2018 | Event News

VideoLinks
Science & Research
Overview of more VideoLinks >>>