6. Department of Medicine and Cancer Research Center, The University of Illinois Hospital and Health Sciences System, Chicago, Illinois, USA.
Abstract
Foxm1 is known as a typical proliferation-associated transcription factor. Here we found that Foxm1 was essential for maintenance of the quiescence and self-renewal capacity of hematopoietic stem cells (HSCs) in vivo in mice. Reducing expression of FOXM1 also decreased the quiescence of human CD34+ HSCs and progenitor cells, and its downregulation was associated with a subset of myelodysplastic syndrome (MDS). Mechanistically, Foxm1 directly bound to the promoter region of the gene encoding the receptor Nurr1 (Nr4a2; called 'Nurr1' here), inducing transcription, while forced expression of Nurr1 reversed the loss of quiescence observed in Foxm1-deficient cells in vivo. Thus, our studies reveal a previously unrecognized role for Foxm1 as a critical regulator of the quiescence and self-renewal of HSCs mediated at least in part by control of Nurr1 expression.

7. Inserm, U866, Dijon, France.
Abstract
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4+ T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.

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Science 31 July 2015: Vol. 349 no pp
Perspective
Cancer
A p53-regulated immune checkpoint relevant to cancer
Laurence Zitvogel1,2,3,4, Guido Kroemer5,6,7,8,9
1Gustave Roussy Cancer Campus, F Villejuif, France.
2INSERM U1015, F Villejuif, France.
3Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France.
4Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, F Villejuif, France.
5Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F Paris, France.
6Université Paris Descartes, Sorbonne Paris Cité, F Paris, France.
7Université Pierre et Marie Curie, F Paris, France.
8Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, F Paris.
9Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, F Villejuif, France.
A major challenge in biomedical research is elucidating connections between stress responses within the cell and the extracellular microenvironment. This dialogue can transcend cellular life, and as such, premortem stress responses condition the mechanism through which corpses are cleared postmortem (1, 2). This implies that the reason why, and the means by which, cells die determine whether their demise ultimately triggers immune responses against dead-cell antigens (3). On page 499 of this issue, Yoon et al. (4) explore the role of p53, a major stress-elicited transcription factor and tumor suppressor protein (5, 6), in the clearance of dying cells by macrophages. The authors determine that p53 operates in a signaling pathway that protects against a systemic, life-threatening autoimmune disease encompassing ulcerative dermatitis, seizures, otitis, eye lesions, and glomerulonephritis (4, 7).

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