Uncoupling cancer mutations reveals critical timing of p53 loss in sarcomagenesis

It is well accepted that cancer develops following the sequential accumulation of multiple alterations, but how the temporal order of events affects tumor initiation and/or progression remains largely unknown. Here, we describe a mouse model that allows for temporally distinct cancer mutations. By integrating a Flp-inducible allele of K-ras[superscript G12D] with established methods for Cre-mediated p53 deletion, we were able to separately control the mutation of these commonly associated cancer genes in vitro and in vivo. We show that delaying p53 deletion relative to K-ras[superscript G12D] activation reduced tumor burden in a mouse model of soft-tissue sarcoma, suggesting that p53 strongly inhibits very early steps of transformation in the muscle. Furthermore, using in vivo RNA interference, we implicate the p53 target gene p21 as a critical mediator in this process, highlighting cell-cycle arrest as an extremely potent tumor suppressor mechanism.National Institutes of Health (U.S.) (grant 5-U01-CA84306)National Cancer Institute (U.S.) (Cancer Center Support (core) Grant P30-CA14051)Howard Hughes Medical Institute (Investigator)Virginia and D.K. Ludwig Fund for Cancer Research (Scholar

ARF Is Not Required for Apoptosis in Rb Mutant Mouse Embryos

AbstractThe retinoblastoma (RB) tumor suppressor gene occupies central roles in cell cycle control and tumor suppression [1]. Homozygous mutant (Rb−/−) embryos die at E13.5–E15.5 [2–4], exhibiting extensive apoptosis and inappropriate S phase entry in the central and peripheral nervous systems, liver, and ocular lens [2–6]. Mice simultaneously mutant for Rb and other genes can be generated to assess the requirement for these genes in cell cycle control and apoptosis. Using such analysis, E2f-1, E2f-3, p53, and Id2 have been identified as important regulators of cell cycle control and apoptosis in Rb−/− embryos [7–10]. Because unrestrained E2F activity in the absence of Rb function contributes to p53-dependent apoptosis in many systems [7, 9, 11–14], we wished to identify genes linking deregulated E2F activity to p53 activation and subsequent apoptosis. As a transcriptional target of E2F-1 [15–18], a regulator of p53 [19–21], and an important mediator of apoptosis [20–26], ARF was a strong candidate for such a role, especially since it can be upregulated in the absence of Rb[21]. From the analysis of Rb/ARF compound mutants we demonstrate that ARF is not an obligatory link between Rb inactivation and p53-dependent apoptosis

Integrin-α5β1 is not required for mural cell functions during development of blood vessels but is required for lymphatic-blood vessel separation and lymphovenous valve formation

Integrin α5β1 is essential for vascular development but it remains unclear precisely where and how it functions. Here, we report that deletion of the gene encoding the integrin-α5 subunit (Itga5) using the Pdgfrb-Cre transgenic mouse line, leads to oedema, haemorrhage and increased levels of embryonic lethality. Unexpectedly, these defects were not caused by loss of α5 from Pdgfrb-Cre expressing mural cells (pericytes and vascular smooth muscle cells), which wrap around the endothelium and stabilise blood vessels, nor by defects in the heart or great vessels, but were due to abnormal development of the lymphatic vasculature. Reminiscent of the pathologies seen in the human lymphatic malformation, fetal cystic hygroma, α5 mutants display defects both in the separation of their blood and lymphatic vasculature and in the formation of the lymphovenous valves. As a consequence, α5-deficient mice develop dilated, blood-filled lymphatic vessels and lymphatic capillaries that are ectopically covered with smooth muscle cells. Analysis of the expression of Pdgfrb during lymphatic development suggests that these defects probably arise from loss of α5β1 integrin in subsets of specialised Prox1+Pdgfrb+ venous endothelial cells that are essential for the separation of the jugular lymph sac from the cardinal vein and formation of the lymphovenous valve leaflets.National Institutes of Health (U.S.) (PO1-HL66105)Cell Migration Consortium (GC11451.126452)National Cancer Institute (U.S.) (Koch Institute Support (core) Grant P30- CA14051)Howard Hughes Medical Institut

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

The RGD-binding α5 and αv integrins have been shown to be key regulators of vascular smooth muscle cell (vSMC) function in vitro. However, their role on vSMCs during vascular development in vivo remains unclear. To address this issue, we have generated mice that lack α5, αv or both α5 and αv integrins on their vSMCs, using the SM22α-Cre transgenic mouse line. To our surprise, neither α5 nor αv mutants displayed any obvious vascular defects during embryonic development. By contrast, mice lacking both α5 and αv integrins developed interrupted aortic arches, large brachiocephalic/carotid artery aneurysms and cardiac septation defects, but developed extensive and apparently normal vasculature in the skin. Cardiovascular defects were also found, along with cleft palates and ectopically located thymi, in Wnt1-Cre α5/αv mutants, suggesting that α5 and αv cooperate on neural crest-derived cells to control the remodelling of the pharyngeal arches and the septation of the heart and outflow tract. Analysis of cultured α5/αv-deficient vSMCs suggests that this is achieved, at least in part, through proper assembly of RGD-containing extracellular matrix proteins and the correct incorporation and activation of latent TGF-β.National Institutes of Health (U.S.) (Grant PO1-HL66105)National Institute of General Medical Sciences (U.S.) (Cell Migration Consortium Grant GC11451.126452)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)Howard Hughes Medical Institut

The genome sequence of the September thorn moth, Ennomos erosaria (Denis & Schiffermüller), 1775

We present a genome assembly from an individual female Ennomos erosaria (the September Thorn moth; Arthropoda; Insecta; Lepidoptera; Geometridae). The genome sequence is 423.1 megabases in span. Most of the assembly is scaffolded into 32 chromosomal pseudomolecules, including the Z and W sex chromosomes. The mitochondrial genome has also been assembled and is 16.3 kilobases in length

GPR56 Plays Varying Roles in Endogenous Cancer Progression

2011 March 29GPR56, a non-classical adhesion receptor, was previously reported to suppress tumor growth and metastasis in xenograft models using human melanoma cell lines. To understand whether GPR56 plays similar roles in the development of endogenous tumors, we analyzed cancer progression in Gpr56 [superscript −/−] mice using a variety of transgenic cancer models. Our results showed that GPR56 suppressed prostate cancer progression in the TRAMP model on a mixed genetic background, similar to its roles in progression of melanoma xenografts. However, its roles in other cancer types appeared to be complex. It had marginal effects on tumor onset of mammary tumors in the MMTV–PyMT model, but had no effects on subsequent tumor progression in either the MMTV–PyMT mice or the melanoma model, Ink4a/Arf [superscript −/−] tyr-Hras. These results indicate diverse roles of GPR56 in cancer progression and provide the first genetic evidence for the involvement of an adhesion GPCR in endogenous cancer development

The genome sequence of the common carpet moth, Epirrhoe alternata (Müller, 1764)

We present a genome assembly from an individual male Epirrhoe alternata (the Common Carpet; Arthropoda; Insecta; Lepidoptera; Geometridae). The genome sequence is 358.5 megabases in span. Most of the assembly is scaffolded into 31 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 16.99 kilobases in length

The genome sequence of the lesser yellow underwing, Noctua comes Hübner, 1813

We present a genome assembly from an individual female Noctua comes (the Lesser Yellow Underwing; Arthropoda; Insecta; Lepidoptera; Noctuidae). The genome sequence is 540.7 megabases in span. Most of the assembly is scaffolded into 32 chromosomal pseudomolecules, including the W and Z sex chromosomes. The mitochondrial genome has also been assembled and is 15.37 kilobases in length. Gene annotation of this assembly on Ensembl identified 18,001 protein coding genes

The genome sequence of the yellow shell moth, Camptogramma bilineatum (Linnaeus, 1758)

We present a genome assembly from an individual male Camptogramma bilineatum (the Yellow Shell; Arthropoda; Insecta; Lepidoptera; Geometridae). The genome sequence is 442.7 megabases in span. Most of the assembly is scaffolded into 30 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 17.04 kilobases in length

Tumor predisposition in mice mutant for p63 and p73: Evidence for broader tumor suppressor functions for the p53 family

Summaryp63 and p73 are functionally and structurally related to the tumor suppressor p53. However, their own role in tumor suppression is unclear. Given the p53-like properties of p63 and p73, we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63+/−;p73+/− mice develop spontaneous tumors. Loss of p63 and p73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and p73 displayed higher tumor burden and metastasis compared to p53+/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported