CHAPEL HILL, N.C. 鈥� Researchers in the 黑料网 found that the protein DAZAP1 plays a key role in the regulation of many genes through a process known as alternative splicing, and when highly expressed in cancer cell line experiments, DAZAP1 was shown to inhibit several types of cancer cells from dividing and moving.
The discovery, published in the journal , marks the first time this little-known protein has been characterized in relation to cancer development and tumor growth.
鈥淚f you knock down DAZAP1, then most of the genes involved in specific cancer cell signaling, cell death, and DNA repair are affected,鈥� said Rajarshi Choudhury, PhD, a postdoctoral research associate in the department of pharmacology and first author of the study. 鈥淚t鈥檚 a domino effect. DAZAP1 seems to be a sort of master regulator.鈥�
The protein regulates how genes are spliced together before the genes produce the proteins that are involved in causing cancer cells to grow and divide. When there鈥檚 a lot of DAZAP1, cancer cells cease proliferating. 鈥淲e鈥檝e seen this in six different types of human cancer cell lines in the lab,鈥� Choudhury said.
Its role as a master regulator is what makes DAZAP1 different from other proteins implicated in cancer and an exciting candidate for further research.
Figure above: Inhibition of MEK/Erk pathway affected nuclear/cytoplasmic translocation of DAZAP1. The cells were transfected with tagged DAZAP1 and hnRNP A1 and detected by corresponding antibodies. Bar, 5鈥壩糾. The percents of cells with DAZAP1localized in nucleus (N), cytoplasm (C) or both compartments (N+C) were counted and plotted in the right panel (n=80 for each sample in two independent experiments).
DAZAP1 is like a commanding officer; other proteins are like soldiers. Many cancer drugs target one of the soldier proteins that have already been expressed from a gene, have received marching orders from other proteins, and are well on their way to causing problems, such as metastasis. Potential cancer drugs that target such soldier proteins sometimes prove ineffective because in some cases cancer cells figure out how to circumvent those proteins and thus the drugs that target those proteins.
DAZAP1, though, is far up the chain of command. It helps organize the genes that will create those soldier proteins. It鈥檚 more of a decision-maker. Yet, Choudhury found that DAZAP1 can still be manipulated. His experiments suggest that certain kinds of cancer cells are able to 鈥渄own regulate鈥� DAZAP1 to allow the cancer cells to divide quickly and relocate. How the cells 鈥渄own regulate鈥� DAZAP1 is not known. In fact, how the protein becomes part of cancer cell biology isn鈥檛 well understood. That will require fully characterizing the protein and figuring out how DAZAP1 senses external signals like nutrients or growth factors that regulate its properties. This could open new avenues of research that will help scientists to better understand formation of certain cancer cell types and how they might be targeted.
(excerpt from 黑料网 New article, April 29, 2014. )
Read the journal article in .
Zefeng Wang, PhD, associate professor of Pharmacology and member of the 黑料网 Lineberger Comprehensive Cancer Center., is senior author on the paper. Other authors include Lee M Graves, PhD, associate professor of pharmacology and member of the 黑料网 Lineberger Comprehensive Cancer Center, postdoctoral fellow Sreerupa Ghose Roy, PhD, graduate student Yihsuan S. Tsai, and Ashutosh Tripathy, PhD, director of the 黑料网 Macromolecular Interactions Facility. Choudhury is currently working with Michael Emanuele, PhD, at the 黑料网 Lineberger Comprehensive Cancer Center.