Rabbit Anti-Human KCND2 Polyclonal antibody

Mice lacking topoisomerase II beta (TopII beta) are known to exhibit a perinatal death phenotype. In the current study, transcription profiles of the brains of wild-type and top2 beta knockout mouse embryos were generated. Surprisingly, only a small number (1 to 4%) of genes were affected in top2 beta knockout embryos. However, the expression of nearly 30% of developmentally regulated genes was either up- or down-regulated. By contrast, the expression of genes encoding general cell growth functions and early differentiation markers was not affected, suggesting that TopII beta is not required for early differentiation programming but is specifically required for the expression of developmentally regulated genes at later stages of differentiation. Consistent with this notion, immunohistochemical analysis of brain sections showed that TopII beta and histone deacetylase 2, a known TopII beta-interacting protein, were preferentially expressed in neurons which are in their later stages of differentiation. Chromatin immunoprecipitation analysis of the developing brains revealed TopII beta binding to the 5' region of a number of TopII beta-sensitive genes. Further studies of a TopII beta-sensitive gene, Kcnd2, revealed the presence of TopII beta in the transcription unit with major binding near the promoter region. Together, these results support a role of TopII beta in activation/repression of developmentally regulated genes at late stages of neuronal differentiation.

Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), is a key regulator of myocyte Ca2+ cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca2+ cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the super-inhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na+ and K+ homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca2+ current, Na+/Ca2+ exchanger, transient outward K+ current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca2+ load and overall Ca2+ dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.