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

Rapid change in drift of the Australian plate records collision with Ontong Java plateau

The subduction of oceanic plateaux, which contain extraordinarily thick basaltic crust and are the marine counterparts of continental flood-basalt provinces, is an important factor in many current models of plate motion1, 2, 3, 4 and provides a potential mechanism for triggering plate reorganization5. To evaluate such models, it is essential to decipher the history of the collision between the largest and thickest of the world's oceanic plateaux, the Ontong Java plateau, and the Australian plate, but this has been hindered by poor constraints for the arrival of the plateau at the Melanesian trench. Here we present 40Ar–39Ar geochronological data on hotspot volcanoes in eastern Australian that reveal a strong link between collision of the Greenland-sized Ontong Java plateau with the Melanesian arc and motion of the Australian plate. The new ages define a short-lived period of reduced northward plate motion between 26 and 23 Myr ago, coincident with an eastward offset in the contemporaneous tracks of seamount chains in the Tasman Sea east of Australia. These features record a brief westward deflection of the Australian plate as the plateau entered and choked the Melanesian trench 26 Myr ago. From 23 Myr ago, Australia returned to a rapid northerly trajectory at roughly the same time that southwest-directed subduction began along the Trobriand trough6. The timing and brevity of this collisional event correlate well with offsets in hotspot seamount tracks on the Pacific plate, including the archetypal Hawaiian chain7, and thus provide strong evidence that immense oceanic plateaux, like the Ontong Java, can contribute to initiating rapid change in plate boundaries and motions on a global scale