Top Stories - Signal Transduction

Human squamous carcinoma cells with ATF2 (green) located at mitochondria (red) after exposure to genotoxic stress. Nuclei are shown in blue.
Molecular switch that allows...

Sanford-Burnham researchers identify protein kinase Cɛ as a molecular switch that determines...

Dr. Gustavo Gutierrez
Getting a handle on cellular...

Some cells divide often (think skin cells), while some, such as most brain cells, almost never do....

MLN4924 kills most cancer cells by binding and inactivating the NEDD8-activating enzyme. NEDD8 and the enzymes that control it are part of the ubiquitin proteasome system. This complex network of enzymes tags proteins with a molecule called ubiquitin. Once it receives this “kiss of death,” a protein is destined for the proteasome, the cell’s "meat grinder." Depending on which proteins are being destroyed, this process helps control almost every aspect of cellular function and is frequently altered in cancer.
Cancer drug’s secret to...

Dr. Matt Petroski and colleagues outline a new method to test a tumor’s resistance to an...

Dr. Elena Pasquale examines Eph receptors.
Sending medicine where it’s...

A collaboration between Sanford-Burnham research Dr. Maurizio Pellecchia and Dr. Elena Pasquale uses...

Meet a cancer researcher: Eric Lau

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On June 5, 2012, California voters will have an opportunity to consider Proposition 29, also known as the California Cancer Research Act. Prop 29’s goal is to provide funding for cancer research by increasing the tax on a pack of cigarettes by $1. Sanford-Burnham’s Board of Trustees endorsed Prop 29 in September 2011. The University of California Regents has also voted to support it, along with the American Cancer Society, American Lung Association, American Heart Association, Stand Up To Cancer, and the Lance Armstrong Foundation (Livestrong).

We are presenting a series of blog posts to allow you to meet some of our cancer researchers and gain a better understanding of how the projected $735 million generated annually by the passing of Prop 29 would benefit cancer research in California.

Meet Eric Lau, Ph.D., a postdoctoral researcher in Sanford-Burnham’s NCI-designated Cancer Center.

Meet a cancer researcher: Matt Petroski

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On June 5, 2012, California voters will have an opportunity to consider Proposition 29, also known as the California Cancer Research Act. Prop 29’s goal is to provide funding for cancer research by increasing the tax on a pack of cigarettes by $1. Sanford-Burnham’s Board of Trustees endorsed Prop 29 in September 2011. The University of California Regents has also voted to support it, along with the American Cancer Society, American Lung Association, American Heart Association, Stand Up To Cancer, and the Lance Armstrong Foundation (Livestrong).

We are presenting a series of blog posts to allow you to meet some of our cancer researchers and gain a better understanding of how the projected $735 million generated annually by the passing of Prop 29 would benefit cancer research in California.

Meet Matthew Petroski, Ph.D., assistant professor in Sanford-Burnham’s NCI-designated Cancer Center.

Cancer drug’s secret to resistance

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Drug resistance is a serious problem for cancer patients—over time, a therapy that was once providing some benefit simply stops working. Sanford-Burnham scientists recently discovered how cancer cells develop resistance to a drug called MLN4924. This experimental therapy is currently being tested in a number of Phase I and Phase I/II clinical trials to determine its efficacy against several different types of cancer, including multiple myeloma, leukemia, and lymphoma.

Published online March 19 by Cell Reports, the study shows that MLN4924-resistant cancer cells escape death because they have a simple mutation in the drug’s target—NEDD8-activating enzyme—that prevents the drug from binding. In unraveling this mechanism, the researchers also developed a relatively quick, low-cost laboratory method that can be used to personalize cancer therapies by predicting how cancer patients will respond to this or other drugs—all before a person starts taking it.

Molecular switch that allows melanoma to resist therapy

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The National Cancer Institute (NCI) estimates that as many as one in 51 men and women will be diagnosed with melanoma—the deadliest form of skin cancer—at some point during their lifetimes. A research team led by Ze’ev Ronai, Ph.D. is working to unravel the molecular mechanisms underlying the development and progression of this disease in hopes of improving prevention and treatment strategies. To do this, Ronai’s laboratory has been studying a protein named Activating Transcription Factor 2 (ATF2), which is associated with poor prognosis in melanoma. ATF2 is a two-faced protein—in melanoma cells, it’s oncogenic, or cancer-causing, while in non-malignant types of skin cancers, it acts as a tumor suppressor.

In a paper published February 3 in the journal Cell, the team identified a molecular switch that controls ATF2’s dual functions. This switch is controlled by protein kinase Cɛ (PKCɛ), which disables ATF2’s tumor-suppressing activities, sensitizing cells to chemotherapy; instead, ATF2’s tumor-promoting activity is enhanced. The team also found that high levels of PKCɛ in melanoma are associated with poor prognosis.

New therapeutic target for heart disease

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Mitochondria are often called cellular “powerhouses” because they convert nutrients into energy. But these tiny structures also help determine cellular lifespan. Scientists are now discovering how mitochondria alternate between duplicating and fragmenting and how these events help cells adapt to diverse physiological conditions.

In a paper published November 18 in Molecular Cell, a team led by Dr. Ze’ev Ronai discovered that the protein Siah2 regulates mitochondrial fragmentation under low oxygen conditions. The significance of these findings is demonstrated by the heart’s response to oxygen shortage and ischemia, the tissue damage caused by lack of oxygen, when the researchers inhibited Siah2. In cells and mice lacking the protein, heart cell death was prevented. As a result, tissue damage was reduced in a mouse model that mimics a heart attack.

Cleaning the cellular house

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When a protein isn’t folded correctly, it can’t function properly. This has the potential to wreak havoc on a cell – and a person. The underlying cause of cystic fibrosis provides a good example of how even a small mistake in protein folding can lead to a big health problem. In this disease, a person inherits a mutated gene encoding a protein called CFTR. Because of this mutation, CFTR is not folded into its proper shape. The cell degrades the misfolded protein, leading to poor lung function, digestive problems and other complications.Most protein folding problems occur when the endoplasmic reticulum (ER) is stressed. The ER is a cellular organelle that specializes in folding proteins that are destined to be anchored in the cell surface or secreted. When the ER’s load of unfolded or misfolded proteins outweighs its ability to fix them, ER stress can result. The cell is usually able to correct this problem by triggering the unfolded protein response. This process slows protein production, enhances protein folding, and clears away any that have been misfolded. ER stress also slows the process of cell division.

“Although it has been observed that ER stress halts cell reproduction, it is not well understood how and why this happens,” explains Dr. Mei-Fan Chen, who recently received her Ph.D. from UC San Diego for research she conducted in Dr. Ze’ev Ronai’s lab.

Sending medicine where it’s needed most

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May is National Cancer Research Month, created by Congress in 2007 to recognize the American Association of Cancer Research (AACR) for its contributions to the field. To honor AACR and highlight some of the important cancer research being done at Sanford-Burnham, we will be posting a series of articles on the ongoing work in our National Cancer Institute-designated Cancer Center. The vast majority of this research is made possible by funding from the National Institutes of Health (NIH), which includes the National Cancer Institute (NCI).

Fighting cancer is one of the most difficult problems humans have ever tackled. Cancer is versatile: it grows rapidly, adapts to difficult environments and hides well. Defeating it will not be easy, but scientists are also taking a versatile approach—one that involves collaborations between many disciplines.

One such collaboration combines the talents of Dr. Elena Pasquale, a biologist, Dr. Maurizio Pellecchia, a chemist and Dr. Paul Fisher, who directs the Institute of Molecular Medicine at Virginia Commonwealth University. Dr. Pasquale has spent years studying the interplay between Eph cell surface receptors and ephrin proteins. Eph receptors are like antennae protruding from the surface of a cell. They foster cell communication by binding to ephrin proteins on the surfaces of neighboring cells. Eph receptors also appear more often in cancer cells than normal ones. Dr. Pasquale and Dr. Pellecchia began to wonder if they could use this deep understanding of Eph/ephrin interactions to create a compound that attaches selectively to Eph and combine it with medicine—creating a guided missile with a potent anti-cancer payload.

Leaders among peers

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Sanford-Burnham scientists are leading several exciting symposia over the next few months. Please follow the links below for more event and registration information.

2011 Signaling, Metabolism and Hypoxia Symposium
Chaired by Dr. Ze’ev Ronai

May 6, 2011, 2:00 – 5:30 p.m. (PDT)
Sanford-Burnham Medical Research Institute
10901 North Torrey Pines Road
La Jolla, California

2011 Glycobiology Gordon Research Conference
Chaired by Dr. Hudson Freeze

May 8 – 13, 2011
Il Ciocco Hotel
Lucca (Barga), Italy

Sanford-Burnham’s 33rd Annual Symposium: Structural Systems Biology
Chaired by members of the Bioinformatics and Systems Biology Program
Drs. Adam Godzik, Dorit Hanein, Andrei Osterman, Niels Volkmann

June 7, 2011, 9:00 a.m. – 5:15 p.m. (PDT)
Hilton La Jolla Torrey Pines
La Jolla, California

Cardiomyocyte Regeneration and Protection
Chaired by Dr. Mark Mercola

Sponsored by Abcam
June 20 – 21, 2011
Hilton La Jolla Torrey Pines
La Jolla, California

2011 Molecular Therapeutics of Cancer Research Conference
Chaired by Dr. Sara Courtneidge

Sponsored by the Cancer Molecular Therapeutics Research Association
July 10 – 14, 2011
Asilomar Conference Center
Pacific Grove, California

Seventh General Meeting of the International Proteolysis Society
Chaired by Dr. Guy Salvesen and Dr. Matthew Bogyo

October 16 – 20, 2011
Hilton San Diego Resort and Spa
San Diego, California

Early steps in melanoma development

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Melanoma is one of the least common types of skin cancer, but it is also the most deadly. Melanocytes (pigment-producing skin cells) lose the genetic regulatory mechanisms that normally limit their number, allowing them to divide and proliferate out of control. One such regulator, called MITF, controls an array of genes that influence melanocyte development, function and survival. Researchers recently used a melanoma mouse model, cell cultures and human tissue samples to unravel the relationship between MITF and ATF2, a transcription factor (or protein that controls gene expression) that is more active in melanomas. The study, published December 23 in PLoS Genetics, demonstrates that the MITF is subject to negative regulation by ATF2, and such regulation is a key determinant in melanoma development. This work also reveals that the ratio of ATF2 to MITF in the nucleus of melanoma cells can predict survival in melanoma patients – relatively high amounts of ATF2 and correspondingly low MITF levels were associated with a poor prognosis.

“In the late 1990s, we began to observe that if you can inhibit ATF2, you can inhibit melanoma,” explained Dr. Ze’ev Ronai, senior author of the study and associate director of Sanford-Burnham’s National Cancer Institute-designated Cancer Center. “This latest study provides the first genetic evidence to support those initial observations. Here we show that mice lacking ATF2 in melanocytes do not develop melanoma even if they carry mutations seen in human melanoma. Moreover, ATF2 expression patterns can predict outcome in melanoma patients.”

A Coming Together of Cancer Centers

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A group of top researchers from the University of Texas MD Anderson Cancer Center (MDACC) gathered with their Sanford-Burnham counterparts in La Jolla last week to seek ways the two Cancer Centers could collaborate to translate basic research into new medicines.

Molecular Dominoes Tip Tumors toward Metastasis

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Why do some tumors stay put while others metastasize? In particularly aggressive forms of prostate cancer, a handful of dangerous cells (known as neuroendocrine-type cells) are to blame. In a study published in the July 13 issue of Cancer Cell, a team of investigators led by Dr. Ze’ev Ronaiand postdoctoral researcher Dr. Jianfei Qi identified a series of molecular events that, like a line of falling dominoes, ultimately leads to the more metastatic neuroendocrine forms of the disease.This study revealed a protein named Siah2 as the first domino to fall – triggering the chain reaction of events that turns a non-malignant tumor into a metastatic neuroendocrine tumor. Members of this Sanford-Burnham research team are now looking for chemical compounds that target Siah2 or other proteins along the chain that leads to the formation of neuroendocrine-type cancer cells. They hope to find a drug that prevents one domino from knocking over the next, halting this series of molecular events and keeping prostate tumors in check.

Getting a handle on cellular JNK

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Some cells divide often (think skin cells), while some, such as most brain cells, almost never do. So it stands to reason that cell division must be precisely regulated – an error at any of several transitions along the way can result in developmental problems or out-of-control cell proliferation, the hallmark of cancer. To assure that the cell cycle – the cell’s process of duplicating its DNA and dividing into two identical ‘daughter’ cells – goes smoothly, a large network of proteins tells other proteins what to do and when to do it. In order to better understand cancerand other diseases, it’s important to map out exactly how the cell cycle works.A new study led by Dr. Ze’ev Ronai, associate director of Sanford-Burnham’s National Cancer Institute-designated Cancer Center, and postdoctoral researcher Dr. Gustavo Gutierrez reveals a new player in cell cycle control. This study, which appeared online in Nature Cell Biology on June 27, showed that JNK, a protein already well known for other reasons, also regulates the cell cycle.

“This was totally unexpected of JNK,” Dr. Gutierrez explained. “We already knew that JNK helps cells respond to stress, such as damage caused by ultraviolet radiation. We thought we already knew how the major components of the cell cycle were regulated. This study really changes the thinking by connecting the two.”