Promyelocytic leukemia zinc-finger (PLZF) is a transcriptional repressor that regulates proliferation, differentiation and apoptosis among various cellular origins. PLZF expression is upregulated in colorectal cancer cell lines but its putative functional role in this context is unknown. Here, we report the identification of a novel p65 PLZF isoform that results from the usage of an evolutionarily conserved alternative translational initiation site. This isoform is devoid of the classical BTB/POZ domain required for nuclear localization and transcriptional repression. Depletion of p65 PLZF expression in colorectal cancer cell lines results in reduction of cell growth, loss of cell anchorage and increase in cell apoptosis. Overall, these results indicate that p65 PLZF is crucial to maintain colorectal cancer cell adhesion as well as survival and must occur independently of the traditionally viewed transcriptional role of PLZF in the course of these biological processes.

The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.

CUX1 is increased in response to inflammatory stress and its nuclear expression is crucial to protect against DSS-induced colitis and subsequent mucosal healing.

NCOR1 is a corepressor that mediates transcriptional repression through its association with nuclear receptors and specific transcription factors. Some evidence supports a role for NCOR1 in neonatal intestinal epithelium maturation and the maintenance of epithelial integrity during experimental colitis in mice. We hypothesized that NCOR1 could control colorectal cancer cell proliferation and tumorigenicity. Conditional intestinal epithelial deletion of Ncor1 in ApcMin/+ mice resulted in a significant reduction in polyposis. RNAi targeting of NCOR1 in Caco-2/15 and HT-29 cell lines led to a reduction in cell growth, characterized by cellular senescence associated with a secretory phenotype. Tumor growth of HT-29 cells was reduced in the absence of NCOR1 in the mouse xenografts. RNA-seq transcriptome profiling of colon cancer cells confirmed the senescence phenotype in the absence of NCOR1 and predicted the occurrence of a pro-migration cellular signature in this context. SOX2, a transcription factor essential for pluripotency of embryonic stem cells, was induced under these conditions. In conclusion, depletion of NCOR1 reduced intestinal polyposis in mice and caused growth arrest, leading to senescence in human colorectal cell lines. The acquisition of a pro-metastasis signature in the absence of NCOR1 could indicate long-term potential adverse consequences of colon-cancer-induced senescence.

Dose-response curves to dopamine were obtained on guinea-pig, dog and human tracheal smooth muscle. Dopamine produced a relaxation of the guinea-pig tracheal chain, and this relaxation was completely blocked by propranolol. The potency of dopamine as a beta-agonist was 1/10 000 that of isoprenaline, 1/250 that of adrenaline and 1/50 that of noradrenaline. In human and dog tracheal smooth muscle, dopamine induced a contraction which could be entirely abolished by alpha-adrenoceptor antagonists. As an alpha-agonist, the potency of dopamine was 1/20 that of adrenaline and noradrenaline. Our data also show that a dopamine induced contraction is greatly potentiated if the smooth muscle specimen has been previously slightly contracted with histamine. We conclude that there are few, if any, specific dopaminergic receptors in the airways. Dopamine acts on both alpha- and beta-adrenoceptors, but in humans and dogs, its effect is predominantly on alpha-adrenoceptors.