Long-Term ERK Inhibition in

Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in -mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of -mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK

Recent advances in the biology and therapy of medullary thyroid carcinoma [version 1; referees: 2 approved]

Medullary thyroid cancer (MTC) is a relatively uncommon yet prognostically significant thyroid cancer. Several recent advances in the biology and current or potential treatment of MTC are notable. These include a new understanding of the developmental biology of the thyroid C cell, which heretofore was thought to develop from the neural crest. RET, encoded by the most common driver gene in MTC, has been shown to be a dual function kinase, thus expanding its potential substrate repertoire. Promising new therapeutic developments are occurring; many have recently progressed to clinical development. There are new insights into RET inhibitor therapy for MTC. New strategies are being developed to inhibit the RAS proteins, which are potential therapeutic targets in MTC. Potential emerging immunotherapies for MTC are discussed. However, gaps in our knowledge of the basic biology of the C cell, its transformation to MTC, and the mechanisms of resistance to therapy impede progress; further research in these areas would have a substantial impact on the field

DeltaNp63alpha overexpression induces downregulation of Sirt1 and an accelerated aging phenotype in the mouse.

p63 is highly expressed in the skin and appears to be an early marker of keratinocyte differentiation. To examine the role of p63 in vivo, we generated transgenic mice that overexpress deltaNp63alpha in the skin. These mice exhibited an accelerated aging phenotype in the skin characterized by striking wound healing defects, decreased skin thickness, decreased subcutaneous fat tissue, hair loss, and decreased cell proliferation. The accelerated skin aging was accompanied by a dramatic decrease in longevity of the mice. We found that aging in deltaNp63alpha transgenic mice and other mouse models correlated with levels of Sirt1, a mammalian SIR2 orthologue thought to extend the lifespan in lower species. Moreover, increased deltaNp63alpha expression induced cellular senescence that was rescued by Sirt1. Our data suggest that deltaNp63alpha levels may affect aging in mammals, at least in part, through regulation of Sirt1

Notch Signaling Induces Rapid Degradation of Achaete-Scute Homolog 1

In neural development, Notch signaling plays a key role in restricting neuronal differentiation, promoting the maintenance of progenitor cells. Classically, Notch signaling causes transactivation of Hairy-enhancer of Split (HES) genes which leads to transcriptional repression of neural determination and differentiation genes. We now report that in addition to its known transcriptional mechanism, Notch signaling also leads to rapid degradation of the basic helix-loop-helix (bHLH) transcription factor human achaete-scute homolog 1 (hASH1). Using recombinant adenoviruses expressing active Notch1 in small-cell lung cancer cells, we showed that the initial appearance of Notch1 coincided with the loss of hASH1 protein, preceding the full decay of hASH1 mRNA. Overexpression of HES1 alone was capable of down-regulating hASH1 mRNA but could not replicate the acute reduction of hASH1 protein induced by Notch1. When adenoviral hASH1 was coinfected with Notch1, we still observed a dramatic and abrupt loss of the exogenous hASH1 protein, despite high levels of ongoing hASH1 RNA expression. Notch1 treatment decreased the apparent half-life of the adenoviral hASH1 protein and increased the fraction of hASH1 which was polyubiquitinylated. The proteasome inhibitor MG132 reversed the Notch1-induced degradation. The Notch RAM domain was dispensable but a lack of the OPA and PEST domains inactivated this Notch1 action. Overexpression of the hASH1-dimerizing partner E12 could protect hASH1 from degradation. This novel function of activated Notch to rapidly degrade a class II bHLH protein may prove to be important in many contexts in development and in cancer