Papers of the Month
By Mahita Kadmiel, Cody Nichols, Kelly Shipkowski, Salahuddin Syed, and Qing Xu
NTP evaluates differences in mammary gland development in rats
Researchers at the National Toxicology Program (NTP) designed a study to evaluate mammary gland development in different strains of rats commonly used in carcinogenicity studies. When scientists evaluate an endocrine disrupting chemical, they can assess the ability of that chemical to affect susceptibility to mammary tumor development when combined with a carcinogen challenge. However, the rate at which the mammary gland develops may differ between rat strains, and this information should be taken into consideration when designing the timing of carcinogen exposure. In this study, the rate of mammary gland development was evaluated in three different strains of rats based on a variety of growth and developmental parameters.
Mammary glands of two of the rat strains, Charles River Sprague Dawley and Charles River Long Evans, developed terminal end buds significantly earlier than the third strain, Harlan Sprague Dawley. These differences in the rate of development differed across the rat strains independently of other factors, such as body weight and timing of vaginal opening, which commonly play a role in development. These results indicate that when designing studies to evaluate susceptibility to mammary carcinogens, appropriate timing must be considered, to properly evaluate the cancer-causing potential of a chemical. (KS)
Stanko JP, Kissling GE, Chappell VA, Fenton SE. 2016. Differences in the rate of in situ mammary gland development and other developmental endpoints in three strains of female rat commonly used in mammary carcinogenesis studies: implications for timing of carcinogen exposure. Toxicol Pathol 44(7):1021−1033.
X-ray crystal structure of a ribosomal biogenesis protein
NIEHS researchers and their collaborators have solved the crystal structure of a protein called Nop9. Nop9 is an RNA-binding protein involved in the production of ribosomes, which are the free or membrane-bound organelles that serve as protein factories of the cell. In addition, the authors discovered that Nop9 plays a crucial role in timing the steps that lead to synthesis of ribosomes. Defects in the manufacture of ribosomes or their function could lead to ribosomopathies, a collection of rare genetic disorders characterized by developmental abnormalities in humans.
The researchers performed X-ray crystallography studies on proteins generated in yeast to identify the structure of Nop9. Because Nop9 is known to interact with ribosomal RNA, the precise site where Nop9 and the target RNA bind to each other was determined by biochemical and molecular methods. Using in vivo studies, the authors discovered that Nop9 functions to prevent precocious maturation of pre-ribosomal RNAs by the timely blocking of their access to certain nucleases. These findings shed light on the molecular basis of ribosomal disorders and may provide knowledge in the development of potential therapeutics. (MK)
Zhang J, McCann KL, Qiu C, Gonzalez LE, Baserga SJ, Hall TM. 2016. Nop9 is a PUF-like protein that prevents premature cleavage to correctly process pre-18S rRNA. Nat Commun 7:13085.
Chromatin remodeler INO80 promotes tumorigenesis in lung cancer
NIEHS researchers and collaborators have discovered that INO80, a chromatin remodeling complex that modifies DNA and protein interactions, and controls gene expression, plays an essential role in the development of non−small-cell lung cancer (NSCLC), a major form of lung cancer. The findings offer both a novel mechanism and a new therapeutic target for lung cancer.
As the leading cause of cancer death worldwide, lung cancer, especially NSCLC, is often resistant to chemotherapy. In search of new treatment targets, the authors explored the function of epigenetic regulators, such as chromatin remodelers, in tumor formation. Their previous study indicated that INO80 activates genes important for embryonic stem cell (ESC) renewal and maintenance. Similar regulatory programs found in ESCs and cancer prompted them to examine the role of INO80 in cancer.
They found that INO80 was overly expressed in lung cancer and upregulated in several NSCLC cell lines compared with normal cells. High expression of INO80 was correlated with a poor prognosis in patients, and silencing INO80 led to suppressed cancer cell proliferation and reduced tumor growth. Because INO80 occupies the enhancer regions of lung cancer-associated genes, it may promote the transcription of these genes and tumorigenesis of lung cancer. (QX)
Zhang S, Zhou B, Wang L, Li P, Bennett BD, Snyder R, Garantziotis S, Fargo DC, Cox AD, Chen L, Hu G. 2016. INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer. Oncogene; doi: 10.1038/onc.2016.311 [Online 19 September 2016].
Role of MARCO in Respiratory Syncytial Virus Disease
NIEHS researchers and their colleagues have found that a mutation in a gene called macrophage receptor with collagenous structure (MARCO) contributes to the severity of respiratory syncytial virus (RSV) disease in humans. RSV may cause respiratory illness in individuals who are immunocompromised and is the leading cause of respiratory tract infection in infants. Lack of a vaccine to treat individuals exposed to RSV has led researchers to use various approaches to identify those who are susceptible to this disease and the potential strategies to prevent it.
Genome-wide association (GWA) studies identified MARCO, which was previously shown to have a protective role in the lungs, as well as other genes associated with viral response, pulmonary inflammation, and cytokine trafficking. Researchers examined mice with and without MARCO, and observed that mice lacking MARCO were unable to prevent pulmonary inflammation resulting from RSV and were at higher risk for disease. They also tested a mutation in human MARCO and found that it was more common in children with severe RSV disease. Although the authors stress that more work is needed to determine how other genes found through GWA contribute to RSV disease, this research will help scientists diagnose individuals at risk for severe RSV disease. (SS)
High M, Cho HY, Marzec J, Wiltshire T, Verhein KC, Caballero MT, Acosta PL, Ciencewicki J, McCaw ZR, Kobzik L, Miller-DeGraff L, Gladwell W, Peden DB, Serra ME, Shi M, Weinberg C, Suzuki O, Wang X, Bell DA, Polack FP, Kleeberger SR. 2016. Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants. EBioMedicine 11:73−84. (Story)
The estrogen receptor mERbeta2 reduces estrogenic activity in mouse models
Characterizing the activity of the mouse-specific estrogen receptor beta2 (mERbeta2), NIEHS scientists determined that the protein has lower activity when binding estrogen compared with its human and rodent counterpart, mERbeta1. They also found that mERbeta2 can regulate mERbeta1 activity by acting as a dominant negative and lowering its responsiveness to endocrine disrupting chemicals (EDCs), which are compounds that disrupt the effectiveness of hormones produced by the body. The study is the first to investigate the regulatory role of mERbeta2 on mERbeta1 after EDC treatment, and suggests researchers should consider the role of mERbeta2 in estrogen signaling when examining mechanisms of toxicity in humans.
The authors measured the amount of mERbeta2 mRNA in mouse tissues and found that it was present in the ovaries, testes, prostate, lung, and colon. They used HepG2 cells to quantify the activity of both mERbeta isoforms in the presence of 16 EDCs, and found that five of them demonstrated estrogenic activity through mERbeta2. In addition, co-expressing mERbeta2 and mERbeta1 decreased ER transactivation compared with mERbeta1 alone. Because there is no human homolog of mERbeta2, this study highlights the need to recognize that its influence on estrogenic activity, determined in mouse models, may not directly apply to some human studies. (CN)
Donoghue LJ, Neufeld TI, Li Y, Arao Y, Coons LA, Korach KS. 2016. Differential activation of a mouse estrogen receptor beta isoform (mERbeta2) with endocrine-disrupting chemicals (EDCs). Environ Health Perspect; doi: 10.1289/EHP396 [Online 16 September 2016].