Navigation Links
Study shows how retinoic acid enters a cell's nucleus

Cornell University researchers have revealed a process that has stumped scientists for many years: exactly how an acid derived from vitamin A enters a cell's nucleus, where it has strong anti-carcinogenic effects.

Discovery of this basic transport mechanism opens a new door for future research on related compounds. The finding has important implications for the fight against cancer and other diseases.

The research, which appears in a recent issue of the journal Molecular Cell (Vol. 18, No. 3), explains for the first time how the cancer-fighting vitamin A derivative retinoic acid (RA) gains entry into a cell's nucleus.

When vitamin A enters a cell's cytoplasm (the portion that lies between the outer membrane and the nucleus), it can be converted to RA, a member of a group of compounds that enter a cell's nucleus and play a role in triggering transcription. This is a basic process for relaying genetic information and switching genes on and off. In this role, RA can inhibit tumor growth. In fact, past clinical trials have shown that RA can help treat leukemia, head, neck and breast cancer. RA and its synthetic derivatives may also be useful in treatment of diabetes, arteriosclerosis and emphysema. Unfortunately, conventional treatments using RA require high, toxic doses, and tumors can develop resistance to the treatment.

Noa Noy, a professor of nutritional sciences at Cornell, and Richard Sessler, the paper's lead author and a graduate student in Noy's lab, wanted to learn how RA is transported into the cell's nucleus. The chemical structure of RA makes it hydrophobic, meaning it is barely soluble in water. But the path from the cell cytoplasm, where RA is made, to the nucleus requires passage through water, a difficult journey for a hydrophobic compound. For RA to rapidly enter a cell's nucleus, it must catch a ride on a water-soluble protein called cellular retinoic acid-binding protein type II (CRABP-II). This protein was discovered o ver two decades ago, but until recently scientists had no idea what it did.

Much like a doorway that requires a pass code to enter, CRABP-II can only move into a cell's nucleus if its amino acids are organized in a certain sequence, called a nuclear localization signal (NLS). However, CRABP-II does not have a recognizable NLS. Researchers have long wondered how proteins without an NLS enter a cell's nucleus.

By comparing the 3-D structures of the CRABP-II protein before and after it comes in contact with RA, Noy and Sessler made a startling discovery: When exposed to RA, three amino acids on the CRABP-II molecule flip their positions, exposing positive charges. Combined with the way the molecule is folded, this area suddenly looks like a classical NLS.

"This discovery creates a precedent for many other proteins that don't have an NLS, and it solves a mystery that has been in the literature for a long time," Noy says. "It explains a basic mechanism of how this protein, CRABP-II, gets into the nucleus, where it can act to suppress tumors."

CRABP-II is a member of a group of proteins called intracellular lipid binding proteins (ILBP), which don't have a recognizable NLS. But now researchers have something new to look for -- folds in a molecule's structure and amino acids that flip when exposed to a hormone or a drug. Noy currently is working with an ILBP that she has pinpointed as a pro-carcinogen -- it promotes cancer. Armed with new tools and knowledge, she hopes to figure out how to suppress the ability of this protein to move to the nucleus and promote cancer, perhaps by blocking the hormone that switches on its NLS.

In previous experiments with mice, Noy and her colleagues showed that by increasing CRABP-II levels within cells, tumor growth rates slow dramatically. The protein transfers RA rapidly and efficiently to the cell's nucleus. In this way, tumor growth may be inhibited using naturally occurring levels of RA, as oppo sed to the toxic doses currently administered.

"If you can provide a bus to get retinoic acid into the nucleus more efficiently, then you enhance its ability to act as an anti-carcinogen," says Noy. "It's a rapid transport advantage."

Her findings emphasize the importance of efforts in structural genomics, the study of the folding motifs in proteins, which allows researchers to compare 3-D structures of seemingly unrelated proteins. "Advances in structural genomics will allow you to predict what the protein does," Noy says.


'"/>

Source:Cornell University News Service


Related biology news :

1. Novel Asthma Study Shows Multiple Genetic Input Required; Single-gene Solution Shot Down
2. Emory Study Tests Bone Marrow Stem Cells to Improve Circulation in Legs
3. UCLA Study Shows One-Third of Drug Ads in Medical Journals Do Not Contain References Supporting Medical Claims
4. Study Demonstrates Gene Expression Microarrays are Comparable and Reproducible
5. Study Links Ebola Outbreaks To Animal Carcasses
6. Breakthrough Microarray-based Technology for the Study of Cancer
7. NYU Study Reveals How Brains Immune System Fights Viral Encephalitis
8. Study finds more than one-third of human genome regulated by RNA
9. Leukemia Drug Breakthrough Study In New England Journal Of Medicine
10. Study identifies predictors of HIV drug resistance in patients beginning triple therapy
11. New Study from Affymetrix Laboratories Points to Changing View of How Genome Works
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:2/8/2017)... NEW YORK , Feb. 8, 2017 /PRNewswire/ ... an individual,s voice to match it against a ... voice such as pitch, cadence, and tone are ... systems require minimal hardware installation, as most PCs ... remotely for different transactions. Voice recognition biometrics are ...
(Date:2/8/2017)... YORK , Feb. 7, 2017 Report Highlights ... The ... should reach $11.4 billion by 2021, growing at a compound ... Includes - An overview of the global markets for synthetic ... 2015, estimates for 2016, and projections of compound annual growth ...
(Date:2/8/2017)... Feb. 7, 2017 Report Highlights ... 2021 from $8.3 billion in 2016 at a compound ... 2021. Report Includes - An overview of the ... trends, with data from 2015 and 2016, and projections ... Segmentation of the market on the basis of product ...
Breaking Biology News(10 mins):
(Date:3/23/2017)... ... March 23, 2017 , ... Advanced Polymer Monitoring Technologies (APMT), ... Sigmund “Sig” Floyd as Vice President ? Global Business Development. Dr. Floyd will ... “Dr. Floyd’s career has spanned 30 years in the chemicals and equipment industries. ...
(Date:3/22/2017)... March 22, 2017 Good Start Genetics, a ... eclipsed the 130 million covered lives mark through its ... Texas . With newly signed contracts ... to enjoy strong payor acceptance based on the quality ... and genetic counseling, its industry-leading customer care and support ...
(Date:3/22/2017)... /PRNewswire/ - FACIT announced a seed stage investment ... start-up created by FACIT focused on developing a ... with non-dilutive capital, achieves a targeted $3.0M financing ... Propellon to accelerate the nomination of a candidate ... entering a strategic partnership for clinical trials in ...
(Date:3/22/2017)... , ... March 21, 2017 , ... ... biologics. To acquire information on the desired increase and/or decrease in antibody-dependent cellular ... for rapid N-glycosylation profiling of therapeutic antibodies. , To meet this demand, ...
Breaking Biology Technology: