Signal Transduction

National Cancer Research Month: Our signal transduction research

by Bruce Lieberman on May 23, 2013 at 6:52 am | 0 Comments

The scientists of our NCI-designated Cancer Center

As you probably know by now – May is National Cancer Research Month, and this is the second post in our blog series to profile cancer research programs underway at Sanford-Burnham. This week, we review a few of the programs that focus on a malfunctioning signaling process in cells called “signal transduction.” Signal transduction occurs when a molecule outside of a cell activates a receptor on the cell, triggering a response inside. This vital process drives a variety of functions, including how a cell senses and responds to environmental change and communicates with other cells. When signal transduction pathways malfunction, a variety of diseases can arise, including cancer.

How some prostate tumors resist treatment—and how it might be fixed

by Heather Buschman, Ph.D. on March 18, 2013 at 9:00 am | 0 Comments

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Siah2 levels (brown staining) are high in human castration-resistant prostate cancer (left), as compared to benign prostate growths (right)

Researchers discover that a protein called Siah2 helps prostate cancer cells resist hormone therapy—making it an attractive biomarker and therapeutic target.

Hormonal therapies can help control advanced prostate cancer for a time. However, for most men, at some point their prostate cancer eventually stops responding to further hormonal treatment. This stage of the disease is called androgen-insensitive or castration-resistant prostate cancer. In a study published March 18 in Cancer Cell, a research team found a mechanism at play in androgen-insensitive cells that enables them to survive treatment. They discovered that a protein called Siah2 keeps a portion of androgen receptors constantly active in these prostate cancer cells. Androgen receptors—sensors that receive and respond to the hormone androgen—play a critical role in prostate cancer development and progression.

Cellular sensor’s 3D structure reveals new clues for combating cancer

Originally published October 23, 2012

Scientists have, for the first time, determined the three-dimensional structure of a complete, unmodified G-protein-coupled receptor (GPCR) in its native environment: embedded in a lipid membrane.

The team, led by Stanley Opella, Ph.D. at the University of California, San Diego and Francesca Marassi, Ph.D. at Sanford-Burnham Medical Research Institute, used a technique called NMR spectroscopy to map the arrangement of atoms in one particular GPCR, called CXCR1. Their finding was published by Nature on October 21.

Cancer drug’s secret to resistance

Originally published March 19, 2012

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.

Cellular sensor’s 3D structure reveals new clues for combating cancer

by admin on October 23, 2012 at 2:05 pm | 0 Comments

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3D structure of CXCR1, a G protein-coupled receptor that transmits inflammatory signals [Image courtesy of Stanley Opella, UCSD]

Scientists have, for the first time, determined the three-dimensional structure of a complete, unmodified G-protein-coupled receptor (GPCR) in its native environment: embedded in a lipid membrane.

What are GPCRs?

Scientists have long known that cells must have some sort of sensor that allows them to detect external signals like aromas, hormones, and neurotransmitters. Adrenalin, for example, hits the outside of a cell yet manages to trigger changes inside the cell—the “flight or fight” response—without actually entering it. For decades, the link between the outside of a cell and the inside remained unknown—until GPCRs were discovered by Robert J. Lefkowitz, M.D. and Brian K. Kobilka, M.D., a finding for which they were awarded the 2012 Nobel Prize in Chemistry earlier this month.

Meet a cancer researcher: Eric Lau

by Kristina Meek on April 13, 2012 at 9:40 am | 0 Comments

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Eric Lau (right) receiving the 2010 Eric Dudl Scholarship Award from CEO Dr. John Reed

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

Meet a cancer researcher: Matt Petroski

by Kristina Meek on March 20, 2012 at 9:37 am | 0 Comments

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Matthew Petroski, Ph.D.

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

Cancer drug’s secret to resistance

by Heather Buschman, Ph.D. on March 19, 2012 at 9:00 am | 0 Comments

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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.

Molecular switch that allows melanoma to resist therapy

by Heather Buschman, Ph.D. on February 2, 2012 at 9:00 am | 2 Comments

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

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

by Heather Buschman, Ph.D. on November 17, 2011 at 11:34 am | 0 Comments

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Hyungsoo Kim, Ph.D., postdoctoral researcher and first author of the study

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

by Heather Buschman, Ph.D. on June 15, 2011 at 3:33 pm | 0 Comments

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Dr. Mei-fan Chen, member of Dr. Ze'ev Ronai's lab

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

by Josh Baxt on May 24, 2011 at 8:03 am | 1 comment

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Dr. Elena Pasquale examines Eph receptors.

Dr. Elena Pasquale studies Eph receptors.

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

by Heather Buschman, Ph.D. on April 29, 2011 at 9:32 am | 0 Comments

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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

by Heather Buschman, Ph.D. on December 23, 2010 at 5:00 pm | 0 Comments

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Anindita Bhoumik, former postdoctoral researcher in the Ronai laboratory

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

by Heather Buschman, Ph.D. on August 4, 2010 at 9:35 am | 0 Comments

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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.

Top Stories - Signal Transduction

National Cancer Research Month: Our signal transduction research

How some prostate tumors resist treatment—and how it might be fixed

Top 10 most-read blog posts of 2012: #1

Cellular sensor’s 3D structure reveals new clues for combating cancer

Top 10 most-read blog posts of 2012: #7

Cancer drug’s secret to resistance

Cellular sensor’s 3D structure reveals new clues for combating cancer

Meet a cancer researcher: Eric Lau

Meet a cancer researcher: Matt Petroski

Cancer drug’s secret to resistance

Molecular switch that allows melanoma to resist therapy

New therapeutic target for heart disease

Cleaning the cellular house

Sending medicine where it’s needed most

Leaders among peers

Early steps in melanoma development

A Coming Together of Cancer Centers

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