The Wild-type p53-induced phosphatase 1, Wip1 (or PPM1D), is unusual in that it is a serine/threonine phosphatase with oncogenic activity. A member of the type 2C phosphatases (PP2Cδ), Wip1 has been shown to be amplified and overexpressed in multiple human cancer types, including breast and ovarian carcinomas. In rodent primary fibroblast transformation assays, Wip1 cooperates with known oncogenes to induce transformed foci. The recent identification of target proteins that are dephosphorylated by Wip1 has provided mechanistic insights into its oncogenic functions. Wip1 acts as a homeostatic regulator of the DNA damage response by dephosphorylating proteins that are substrates of both ATM and ATR, important DNA damage sensor kinases. Wip1 also suppresses the activity of multiple tumor suppressors, including p53, ATM, p16 INK4a and ARF. We present evidence that the suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.

The intestine has an extraordinary capacity for fatty acid (FA) absorption. Numerous candidates for a protein-mediated mechanism of dietary FA absorption have been proposed, but firm evidence for this process has remained elusive. Here we show that the scavenger receptor CD36 is required both for the uptake of very long chain FAs (VLCFAs) in cultured cells and the absorption of dietary VLCFAs in mice. We found that the fraction of CD36-dependent saturated fatty acid association/absorption in these model systems is proportional to the FA chain length and specific for fatty acids and fatty alcohols containing very long saturated acyl chains. Moreover, intestinal VLCFA absorption is completely abolished in CD36-null mice fed a high fat diet, illustrating that the predominant mechanism for VLCFA absorption is CD36-dependent. Together, these findings represent the first direct evidence for protein-facilitated FA absorption in the intestine and identify a novel therapeutic target for the treatment of diseases characterized by elevated VLCFA levels.In typical Western diets, the bulk of the calories exist in the chemical form of triacylglycerols (TAGs) 4 that consist of glycerol esterified to three fatty acid (FA) molecules. Once consumed, the FAs are liberated from TAG via pancreatic enzymes and are quantitatively absorbed by the body for energy, storage, and other cellular processes. The mechanism(s) responsible for the absorption of dietary FAs have not been well characterized. Given the extraordinary capacity of the gut for FA absorption, it seems likely that diffusion plays a major role in this process. The most common fatty acids in a typical diet are the long chain FAs palmitate (16:0) and oleate (18:1), which have relatively high rates of simple diffusion in model membrane systems (reviewed in Ref. 1).Unlike the long chain FAs, saturated very long chain FAs (VLCFAs) are much less soluble in aqueous environments, and the diffusion rates are much lower. In mixtures of vesicles and albumin (which model FA delivery to peripheral cells such as adipocytes), VLCFAs partition more favorably into phospholipid bilayers compared with long chain FAs (2). In addition, the dissociation of saturated VLCFAs from model vesicles is 10 5 -10 6 -fold slower than the dissociation of long chain FAs (3). This combination of preferential partitioning and slow dissociation suggests that protein-based mechanisms may be required for efficient absorption and utilization of VLCFAs in peripheral tissues in vivo.In contrast to peripheral absorption, VLCFA absorption in the intestine is essentially an unstudied field. The only direct experimentation to date was published in 1963 wherein Fields and Gatt (4) determined that intragastric or intraduodenal [ 14 C]lignoceric acid (24:0) was absorbed in the rat intestine and appeared in the lymph primarily in the neutral glyceride fraction (i.e. triacylglycerol). Since then, intestinal fatty acid absorption has been primarily studied using only long chain FAs and often employed indirect measures su...

In response to DNA double strand breaks, the histone variant H2AX at the break site is phosphorylated at serine 139 by DNA damage sensor kinases such as ataxia telangiectasia-mutated, forming ␥-H2AX. This phosphorylation event is critical for sustained recruitment of other proteins to repair the break. After repair, restoration of the cell to a prestress state is associated with ␥-H2AX dephosphorylation and dissolution of ␥-H2AX-associated damage foci. The phosphatases PP2A and PP4 have previously been shown to dephosphorylate ␥-H2AX. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (WIP1) also dephosphorylates ␥-H2AX at serine 139 in vitro and in vivo. Overexpression of WIP1 reduces formation of ␥-H2AX foci in response to ionizing and ultraviolet radiation and blocks recruitment of MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1) to DNA damage foci. Finally, these inhibitory effects of WIP1 on ␥-H2AX are accompanied by WIP1 suppression of DNA double strand break repair. Thus, WIP1 has a homeostatic role in reversing the effects of ataxia telangiectasia-mutated phosphorylation of H2AX.

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