Biology subjects

Gartner, F.

Publications and source records attributed to Gartner, F..

3 recordsLinked to original sources

bioRxiv2023

Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer

KRAS hotspot mutations are difficult to target, highlighting the need of developing new specific target drugs for cancers driven by these mutations, like colorectal cancer (CRC). Here, we discover a new ruthenium compound, PMC79, that inhibits specifically mutated KRAS and the downstream signaling ERK and AKT proteins both "in vitro" and "in vivo". We demonstrated that PMC79 inhibits KRAS mutated kinase activity and is selective for KRAS mutations not affecting the KRAS wild-type protein. KRAS inhibition is not dependent on actin polymerization or on proteasome. Molecular docking analysis suggests that this effect might result from protein dynamics associated with the mutations. We demonstrated that low doses of PMC79 potentiate 5-fluorouracil anticancer effect. "In vivo" PMC79 "proof of concept" showed that it reduces tumor growth in the CAM-xenograft model and induces necrosis of the tumor in the xenograft mice model. PMC79 is a promising new "magic bullet" for CRCs harboring mutated KRAS.

pharmacology and toxicology↗

bioRxiv2023

Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease

The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabAs binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.

immunology↗

bioRxiv2022

The dual character of the inhibitory functions of CD6

T-cell membrane scaffold proteins play important roles in T cell biology, functioning as multi-functional signaling hubs. CD6 assembles a large intracellular signalosome but, unlike typical membrane-attached scaffolds like LAT or PAG, it has a sizeable ectodomain that binds a well-characterized ligand, CD166. It is unclear whether CD6 has net inhibitory or costimulatory functions or how its ectodomain influences these activities. To explore these questions, we dissected the signaling functions of the extracellular and cytoplasmic regions of CD6. We found that CD6 was delivered to the immunological synapse and suppressed T cell responsiveness in vitro wholly dependently of its cytoplasmic domain, indicating that CD6 very potently imposes tonic inhibition, acting as a structural and signaling inhibitory hub. However, the cell-intrinsic suppression of autoimmunity by CD6 in vivo was also impacted by extracellular interactions, demonstrated by the increased susceptibility of mice to experimental autoimmune encephalomyelitis after removal of the ligand binding region of the ectodomain of CD6. Our work identifies CD6 as a new class of on/off switching scaffold-receptor that constrains immune responsiveness at two speeds. First, it sets signaling thresholds via tonic inhibition, functioning as a cytoplasmic membrane-bound scaffold and, second, by cycling between signaling-enabling and signalinginhibiting ectodomain isoforms it functions as an immune checkpoint.

immunology↗