Re: [GRG] rescuer for PTEN – M. D. Anderson Cancer Center

http://www.eurekalert.org/pub_releases/2013-11/uotm-mar112713.php

27-Nov-2013

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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center

MD Anderson researchers identify a rescuer for vital tumor-
suppressor

Enzyme intervenes when cancer-fighting PTEN is bound for cell’s
protein-destroying machinery

HOUSTON – A protector for PTEN, a tumor-thwarting protein often
missing in cancer cells, has emerged from research led by
scientists at The University of Texas MD Anderson Cancer Center
published online at Nature Cell Biology this week.

“We discovered that the enzyme USP13 stabilizes the PTEN protein by
reversing a process that marks various proteins for destruction by
the cell’s proteasome,” said the paper’s senior author Li Ma,
Ph.D., assistant professor of Experimental Radiation Oncology.

“USP13 also suppresses tumor formation and glycolysis though PTEN,”
Ma said. Glycolysis is a glucose metabolism pathway that tumors
rely on to thrive and grow.

After establishing the relationship in cell lines and mouse model
experiments, the team found low levels of USP13 in human breast
tumors correlate with lower levels of PTEN. Both proteins were more
abundantly present in normal breast tissue.

PTEN regulates cell growth and division. It also inhibits signaling
by the AKT molecular pathway, which is involved in cell survival,
metabolism and growth and is often overactive in human cancers.

This discovery provides a new way to think about PTEN deficiency
and how it might be remedied. Ma noted the likely keys to possible
treatment would be identifying druggable oncogenes that suppress
USP13 in cancer cells, or hitting targets usually controlled by
PTEN.

“In our paper, we showed that loss of USP13 leads to loss of PTEN
and activation of AKT signaling, and that treatment of a breast
cancer cell line with the AKT inhibitor MK-2206 can abolish the
effect of USP13 loss on promoting tumor cell proliferation,” Ma
said. MK-2206 is actively being tested in clinical trials against a
variety of cancers at MD Anderson and elsewhere, including advanced
breast cancer.

Genetic defects alone don’t explain PTEN’s absence

“The rationale of our work is that despite the frequent genetic
alterations seen in the PTEN gene in human cancer, loss of the PTEN
protein has been observed in a much higher percentage of human
tumors,” Ma said. “For example, approximately 5 percent of non-
inherited breast tumors carry PTEN gene mutations, but loss of the
PTEN protein is actually reported in nearly 40 percent of breast
tumors.”

This suggested, Ma said, that regulation of PTEN after gene
expression or after its translation into a protein “may contribute
substantially to development of human breast cancer.”

Ma and colleagues focused on ubiquitylation, a process that
regulates proteins by attaching molecules called ubiquitins to
them. When more than one ubiquitin is attached to a protein, a
chain forms that is both a target and a handle for the proteasome –
a protein complex that degrades proteins and recycles bits of them
for other use.

Previous studies had revealed several proteins that attach
ubiquitins to PTEN to initiate its destruction. Nothing had been
identified that reverses that process for PTEN.

Auditioning 30 DUBs to find one PTEN defender

The team screened 30 known deubiquitylating enzymes (DUBs). Of
those, USP13 was noteworthy for its ability to stabilize PTEN by
directly binding to it and removing ubiquitins.

A series of experiments showed that overexpressing USP13 in breast
cancer cells:

• Increased PTEN expression and decreased cell multiplication and
conversion to a cancerous state.
• Reduced cancer-promoting AKT signaling.
• Had no effect in cancer cells that lacked the PTEN gene.

The team also confirmed that USP13 removes ubiquitins from PTEN.
Silencing USP13 expression tripled the polyubiquitylation of PTEN,
expressing USP13 reduced it by 65 percent.

Knocking down USP13 in breast cancer cells increased cell
multiplication and growth, while restoring either PTEN or USP13
completely reversed the effect.

Lower USP13, larger tumors in mice

In mice, those implanted with a breast cancer cell line with USP13
depleted had a 2.5-fold increase in tumor volume and a 3.5-fold
increase in tumor weight over 65 days compared with a control group.

Ma and colleagues also analyzed USP13 and PTEN using human breast
cancer progression tissue microarrays from the National Cancer
Institute.

• Lower PTEN levels were found in 152 of 206 tumors (73.8 percent)
and lower USP13 levels in 83 of 201 (41.3 percent).
• Of the 83 tumors with low USP13, 73 (88 percent) also had low
PTEN.
• In normal breast tissue, only 31.8 percent had low levels of
PTEN; 13.2 percent had low USP13.

“Our future studies aim to determine the physiological function of
USP13 and how USP13 expression is lost in human cancer,” Ma said.

###

Co-authors with Ma are first author Jinsong Zhang, Ph.D., Peijing
Zhang, Ph.D., Hai-long Piao, Ph.D., Wenqi Wang, Ph.D., Min Wang,
Dahu Chen, Ph.D. and Junjie Chen, Ph.D., of MD Anderson’s
Department of Experimental Radiation Oncology; Yongkun Wei, Ph.D.,
Yutong Sun, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson’s
Department of Molecular and Cellular Oncology; and Subbareddy
Maddika, Ph.D., of the Laboratory of Cell Death and Cell Survival,
Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad,
India.

Grants from the National Cancer Institute of the U.S. National
Institutes of Health (R00CA138572 and R01CA166051) and a Cancer
Prevention and Research Institute of Texas Scholar Award to Ma
funded this research. MD Anderson receives a cancer center support
grant from the NCI (P30 CA016672).

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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