Featured Research

from universities, journals, and other organizations

Required Activation "Cascade" Identified For P53 Tumor-Suppressor Protein

Date:
December 25, 2001
Source:
Wistar Institute
Summary:
Researchers at The Wistar Institute have identified a carefully orchestrated series of molecular modifications to p53 that must occur for it to perform its normal function, which is to initiate the transcription of genes involved in growth control. The findings give a clearer picture of the system in which p53 is a central player and may suggest new ways to combat an array of cancers in which p53 is dysfunctional.

PHILADELPHIA - The innocuously named protein p53 is among the most vital of molecules for regulating cell growth in the human body, and it represents one of the body's leading defenses against the uncontrolled growth of cancers as a result. Damaged variants of the tumor-suppressor p53 protein have been found in more than half of human cancers. Now, in a new study, researchers at The Wistar Institute have identified a carefully orchestrated series of molecular modifications to p53 that must occur for it to perform its normal function, which is to initiate the transcription of genes involved in growth control. The findings give a clearer picture of the system in which p53 is a central player and may suggest new ways to combat an array of cancers in which p53 is dysfunctional. More generally, the study begins to show how many other proteins that act directly on DNA, as p53 does, might also be tightly managed by similar sets of closely interacting molecules. A report on the research appears in the December issue of Molecular Cell, published today.

Related Articles


"Our findings show that p53's ability to suppress tumors depends on a cascade of molecular changes that occur after the molecule binds to the DNA," says Shelley L. Berger, Ph.D., an associate professor in molecular genetics and senior author on the report. "The data also outline a general mechanism by which many DNA-binding proteins, including other transcription factors like p53, might be regulated. So, in terms of understanding gene control, the implications could be quite broad."

The normal function of p53 is to monitor the replication of DNA during the cycle of cell division. If DNA damage is detected, p53 is responsible for either arresting the cycle until repairs can be made or sending the cell into apoptosis, or regulated cell death. When p53 is unable to perform this function, the frequent result is cancerous growth of the cell.

Earlier work by Berger and others, including Wistar associate professor Thanos Halazonetis, D.D.S., Ph.D., a coauthor on the current study, had shown that p53 uses a family of molecules called HATs, or histone acetyltransferases, to activate the genes that it controls. HATs, which act on small proteins called histones, are themselves at heart of larger understanding of gene control that is still developing.

In this emerging scheme, long strands of DNA are seen to coil themselves around histones to create sub-chromosomal structures called nucleosomes. Genes along the tightly wrapped DNA cannot be physically accessed by the cellular machinery of transcription, and so their expression is repressed. The coils of DNA around the histones must first be loosened to permit gene expression. HATs are enzymes that add an acetyl molecule to the histone, which has the effect of loosening the DNA coils.

To further explore HAT activity in relation to p53, Berger and her colleagues created mutations at the four specific sites on p53 where HATs are known to acetylate the molecule, thus disabling the process.

"What we found was that the mutations at p53's acetylation sites significantly reduced its efficiency as a transcriptional activator and almost entirely abrogated its ability to arrest the cell cycle," says Wistar staff scientist Nickolai A. Barlev, Ph.D., lead author on the Molecular Cell study. "This was the first direct evidence that acetylation is critical for p53's function."

"While we saw no effect on p53's ability to bind to DNA," says Berger, "the molecule was severely limited in its ability to activate transcription without the acetylation events that would ordinarily follow binding to DNA. We also demonstrated the acetylation process to be multi-step: acetylation of p53 triggers the histone acetylation required to promote gene transcription."

In addition to senior author Berger, lead author Barlev, and collaborating coauthor Halazonetis, the remaining coauthors on the Molecular Cell study are Lin Liu, Nabil H. Chehab, Kyle Mansfield, and Kimberly G. Harris, all at The Wistar Institute. The research was supported by a National Cancer Institute grant.

The Wistar Institute is an independent nonprofit research institution dedicated to discovering the causes and cures for major diseases, including cancer and AIDS. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1968, and one of only 10 focused on basic research. Founded in 1892, Wistar was the first independent institution devoted to medical research and training in the nation. Since the Institute's inception, Wistar scientists have helped to improve world health through the development of vaccines against rabies, rubella, rotavirus, cytomegalovirus, and other viruses and the identification of genes associated with breast, lung, prostate and other cancers.


Story Source:

The above story is based on materials provided by Wistar Institute. Note: Materials may be edited for content and length.


Cite This Page:

Wistar Institute. "Required Activation "Cascade" Identified For P53 Tumor-Suppressor Protein." ScienceDaily. ScienceDaily, 25 December 2001. <www.sciencedaily.com/releases/2001/12/011225094237.htm>.
Wistar Institute. (2001, December 25). Required Activation "Cascade" Identified For P53 Tumor-Suppressor Protein. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2001/12/011225094237.htm
Wistar Institute. "Required Activation "Cascade" Identified For P53 Tumor-Suppressor Protein." ScienceDaily. www.sciencedaily.com/releases/2001/12/011225094237.htm (accessed November 26, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, November 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

Newsy (Nov. 25, 2014) The US FDA is announcing new calorie rules on Tuesday that will require everywhere from theaters to vending machines to include calorie counts. Video provided by Newsy
Powered by NewsLook.com
Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Newsy (Nov. 25, 2014) Need another reason to eat yogurt every day? Researchers now say it could reduce a person's risk of developing type 2 diabetes. Video provided by Newsy
Powered by NewsLook.com
Madagascar Working to Contain Plague Outbreak

Madagascar Working to Contain Plague Outbreak

AFP (Nov. 24, 2014) Madagascar said Monday it is trying to contain an outbreak of plague -- similar to the Black Death that swept Medieval Europe -- that has killed 40 people and is spreading to the capital Antananarivo. Duration: 00:42 Video provided by AFP
Powered by NewsLook.com
Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) A new study links greater authority with increased depressive symptoms among women in the workplace. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins