Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development

Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer

The influence of delay in mononuclear cell isolation on acute myeloid leukemia phosphorylation profiles

Mass-spectrometry (MS) based phosphoproteomics is increasingly used to explore aberrant cellular signaling and kinase driver activity, aiming to improve kinase inhibitor (KI) treatment selection in malignancies. Phosphorylation is a dynamic, highly regulated post-translational modification that may be affected by variation in pre-analytical sample handling, hampering the translational value of phosphoproteomics-based analyses. Here, we investigate the effect of delay in mononuclear cell isolation on acute myeloid leukemia (AML) phosphorylation profiles. We performed MS on immuno-precipitated phosphotyrosine (pY)-containing peptides isolated from AML samples after seven pre-defined delays before sample processing (direct processing, thirty minutes, one hour, two hours, three hours, four hours and 24 h delay). Up to four hours, pY phosphoproteomics profiles show limited variation. However, in samples processed with a delay of 24 h, we observed significant change in these phosphorylation profiles, with differential phosphorylation of 22 pY phosphopeptides (p < 0.01). This includes increased phosphorylation of pY phosphopeptides of JNK and p38 kinases indicative of stress response activation. Based on these results, we conclude that processing of AML samples should be standardized at all times and should occur within four hours after sample collection

Aseismic zone and earthquake segmentation associated with a deep subducted seamount in Sumatra

The subduction of large topographic features such as seamounts has been linked to plate locking1-7, earthquake generation8 and segmentation6, as well as crustal erosion9,11 at subduction zones. However, the role of subducted features in the generation of megathrust earthquakes has been difficult to discern because traditional imaging techniques are limited to the upper 12 km of the Earth's crust12, whereas these ruptures initiate at depths of 20-40 km (ref. 13). Here we use a deeply penetrating imaging technique with a low-energy source to identify a seamount 3-4 km high and 40 km wide that has been subducted to a depth of 30-40 km below the Sumatra forearc mantle. We find that the seamount has remained intact despite more than 160 km of subduction, and that there is no seismic activity either above or below the seamount. We therefore conclude that the coupling between the seamount and overriding plate is weak and aseismic 14. We suggest that the subduction of a topographic feature such as a seamount could lead to the segmentation of the subduction zone, which could in turn reduce the maximum size of megathrust earthquakes in these localities. © 2011 Macmillan Publishers Limited. All rights reserved