Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation.

The E3 ubiquitin ligase Mule is often overexpressed in human colorectal cancers, but its role in gut tumorigenesis is unknown. Here, we show in vivo that Mule controls murine intestinal stem and progenitor cell proliferation by modulating Wnt signaling via c-Myc. Mule also regulates protein levels of the receptor tyrosine kinase EphB3 by targeting it for proteasomal and lysosomal degradation. In the intestine, EphB/ephrinB interactions position cells along the crypt-villus axis and compartmentalize incipient colorectal tumors. Our study thus unveils an important new avenue by which Mule acts as an intestinal tumor suppressor by regulation of the intestinal stem cell niche.

Depositional history of organic contaminants in Narragansett Bay, Rhode Island, USA.

Sediment cores were taken at three locations in Narragansett Bay, Rhode Island, USA in 1997 and analyzed for a variety of organic contaminants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), chlordanes, linear alkyl benzenes (LABs), benzotriazoles (BZTs) and dichlorodiphenyltrichloroethanes (DDTs) and metabolites. The distributions of these chemicals at Apponaug Cove and in the Seekonk River indicate that there was a disturbance in the depositional environment relative to cores collected at these locations in 1986 demonstrating the potential for buried contaminants to be remobilized in the environment even after a period of burial. Sharp breaks in the concentration of several organic markers with known dates of introduction were successfully used to determine the sedimentation rate at Quonset Point. Both the Quonset Point and Seekonk River cores had subsurface maximums for DDTs, PCBs, PAHs and BZTs, which are consistent with expected inputs to the environment. The Apponaug Cove core showed an increase of most contaminants at the surface indicating a recent event in which more contaminated sediments were deposited at that location.

Tributyltin in environmental samples from the Former Derecktor Shipyard, Coddington Cove, Newport RI.

Tributyltin (TBT) was detected in all 24 surface sediment (top 2 cm) samples collected from Coddington Cove, Newport, RI. TBT surface sediment concentrations ranged from 32 to 372 ng Sn/g with a mean concentration of 146 ng Sn/g. Analyses of selected core sections detected TBT in at least the top 18 cm at all 7 stations where cores were collected. No consistent TBT concentration trends with depth for these cores suggest mixing is an important process in the sediment column. In one core (station 28), TBT was found in the 76-86 cm section at a concentration of 141 ng Sn/g; thus sediments are a significant sink for TBT. However, sediment mixing processes can enhance releases of bioavailable TBT. Mussels, clams and fish from Coddington Cove contain TBT at concentrations ranging from 9.2 to 977 ng Sn/g. TBT concentrations in lobsters were below the detection limit (<6 ng Sn/g). Based on available screening criteria, TBT concentrations in Coddington Cove sediment is likely to be having an adverse effect on the biota at some locations.

Polychlorinated biphenyls in Narragansett Bay surface sediments.

Polychlorinated biphenyls (PCBs) were evaluated in 41 surface sediments collected from Narragansett Bay, RI in 1997-1998. Highest concentrations of total PCBs (1760 ng/g) were in rivers at the head of the bay and the values decreased southward toward the mouth of the bay, with elevated concentrations in some of the coves. The PCB levels in approximately 43% of the samples exceeded the effects range median (ERM) guideline [Environ. Manage. 19 (1995) 81] indicating possible adverse biological effects at these stations. Principal component analysis (PCA) of the surface sediment PCBs separated the Taunton River samples from the rest of the samples. This result suggests that this river has a different PCB composition and sources than the other areas investigated. It also showed that this river has a limited influence on other bay stations as the adjacent samples downstream did not have the same chemical signature. Congener ratios derived from the PCA were useful in distinguishing stations that had different sources of PCBs than the bulk of the bay sediments. Although Aroclor 1268 and 1270 accounted for <1% of all PCB production, their major components, CB206 and CB209, account for 3-6% of the CBs in most bay samples. This may reflect more local use of these Aroclor mixtures and/or be indicative of their relative stability, compared to less chlorinated mixtures. Using linear alkyl benzenes (LABs) as a marker for sewage derived PCBs suggested that up to 95% of the PCBs at the most contaminated sites in the Seekonk, Providence, and Taunton Rivers were sewage derived. This analysis also showed that there is a high background level (167 ng/g) of PCBs in the Seekonk and Providence River, while the Taunton River had a relatively low background level (23.7 ng/g). At the furthest stations south in the Providence River, the sewage derived PCBs only accounted for 23% of the total which suggests that PCB associated with sewage particles are rapidly deposited and are therefore not the most significant source of these compounds to the lower reaches of Narragansett Bay.

The distribution and sources of polycyclic aromatic hydrocarbons in Narragansett Bay surface sediments.

Polycyclic aromatic hydrocarbons (PAHs) were measured in 41 surface sediments from Narragansett Bay, RI. All the analytes generally decrease down bay from the Seekonk, Providence and Taunton Rivers at the head of the bay. Total PAHs ranged from 0.569 to 216 microg/g with 27% exceeding the effects range median (ERM) of 44.8 microg/g and 73% of the stations exceeding the effects range low (ERL) of 4.02 microg/g (Long et al., 1995). Based on principal component analysis, the major source of the contaminants in Narragansett Bay was the Providence River while the coves and Taunton River/Mt. Hope Bay appeared to only have a limited influence on the open bay. PAH source ratios indicate that creosote and/or coal may be the most significant contributor of pyrogenic high molecular weight PAHs in Narragansett Bay, along with significant contributions from diesel exhaust.