16 research outputs found
Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity
The mammalian circadian system consists of a central oscillator in the suprachiasmatic nucleus of the hypothalamus, which coordinates peripheral clocks in organs throughout the body. Although circadian clocks control the rhythmic expression of a large number of genes involved in metabolism and other aspects of circadian physiology, the consequences of genetic disruption of circadian-controlled pathways remain poorly defined. Here we report that the targeted disruption of Nocturnin (Ccrn4l) in mice, a gene that encodes a circadian deadenylase, confers resistance to diet-induced obesity. Mice lacking Nocturnin remain lean on high-fat diets, with lower body weight and reduced visceral fat. However, unlike lean lipodystrophic mouse models, these mice do not have fatty livers and do not exhibit increased activity or reduced food intake. Gene expression data suggest that Nocturnin knockout mice have deficits in lipid metabolism or uptake, in addition to changes in glucose and insulin sensitivity. Our data support a pivotal role for Nocturnin downstream of the circadian clockwork in the posttranscriptional regulation of genes necessary for nutrient uptake, metabolism, and storage
Regulation of Nuclear Lamin Polymerization by Importin α*
Nuclear lamins are integral components of the nuclear envelope and are
important for the regulation of many aspects of nuclear function, including
gene transcription and DNA replication. During interphase, the lamins form an
intranuclear intermediate filament network that must be disassembled and
reassembled when cells divide. Little is known about factors regulating this
assembly/disassembly cycle. Using in vitro nuclear assembly and lamin
assembly assays, we have identified a role for the nuclear transport factor
importin α in the regulation of lamin assembly. Exogenous importin
α inhibited nuclear lamin assembly in Xenopus interphase egg
nuclear assembly assays. Fractionation of the egg extract used for nuclear
assembly identified a high molecular weight complex containing the major egg
lamin, XLB3, importin α, and importin β. This complex could be
dissociated by RanGTP or a competing nuclear localization sequence, indicating
that lamin assembly is Ran- and importin α-dependent in the egg extract.
We show that the addition of importin α to purified lamin B3 prevents
the assembly of lamins in solution. Lamin assembly assays show that importin
α prevents the self-association of lamins required to assemble lamin
filaments into the typical paracrystals formed in vitro. These
results suggest a role for importin α in regulating lamin assembly and
possibly modulating the interactions of lamins with lamin-binding
proteins
Lamin A/C deficiency is an independent risk factor for cervical cancer
In the past, cervical cancer has been linked to Human Papilloma Virus (HPV) infection. Previously, we found that pre-neoplastic breast and ovarian lesions may be associated with lamin A/C deficiency, resulting in abnormal nuclear morphologies and chromosomal instability. Ultimately, these phenomena are thought to lead to cancer. Here, we assessed lamin A/C deficiency as an indicator for the risk to develop cervical cancer.
The expression of lamin A/C was assessed by Western blotting in cervical uterine smears (CUS) of 76 adult women from Benin concomitant with nuclear morphology assessment and HPV genotyping using microscopy and PCR-based assays, respectively. In vitro analyses were performed to uncover the mechanism underlying lamin A/C expression alterations observed in vivo. The presence of cervical intra-epithelial neoplasia (CIN) was assessed by colposcopy.
Normal lamin A/C expression (group A) was observed in 39% of the CUS, weak lamin A/C expression (group B) was observed in 28% of the CUS and no lamin A/C expression (group C) was observed in 33% of the CUS tested. Infection with oncogenic HPV was found to be significantly higher in group C (36%) than in groups A (17%) and B (14%). Two years after our first assessment, CIN was observed in 20% of the women in group C. The in vitro application of either a histone deacetylase inhibitor (trichostatin) or a protein kinase inhibitor (staurosporine) was found to restore lamin A/C expression in cervical cancer-derived cells.
Lamin A/C deficiency may serve as an independent risk factor for CIN development and as an indicator for preventive therapy in cervical cancer