Wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene. Although the normal roles of tumour suppressor genes are still largely unknown, it seems that they could be involved in promoting cell differentiation as well as in mediating growth arrest by growth-inhibitory cytokines. Hence, the abrogation of wild-type p53 expression, which is a common feature of many tumours, could eliminate these activities. We have now tested this notion by restoring the expression of p53 in a murine myeloid leukaemic cell line that normally lacks p53. The use of a temperature-sensitive p53 mutant allowed us to analyse cells in which the introduced p53 had either wild-type or mutant properties. Although there seemed to be no effect on differentiation, the introduction of wild-type p53 resulted in rapid loss of cell viability in a way characteristic of apoptosis (programmed cell death). The effect of wild-type p53 was counteracted by interleukin-6. Thus products of tumour suppressor genes could be involved in restricting precursor cell populations by mediating apoptosis.

Activation of naive CD8 + T cells with antigen induces their differentiation into effector cytolytic T lymphocytes (CTLs

The RUNX transcription factors are important regulators of lineagespecific gene expression. RUNX are bifunctional, acting both as activators and repressors of tissue-specific target genes. Recently, we have demonstrated that Runx3 is a neurogenic transcription factor, which regulates development and survival of proprioceptive neurons in dorsal root ganglia. Here we report that Runx3 and Runx1 are highly expressed in thymic medulla and cortex, respectively, and function in development of CD8 T cells during thymopoiesis. Runx3-deficient (Runx3 KO) mice display abnormalities in CD4 expression during lineage decisions and impairment of CD8 T cell maturation in the thymus. A large proportion of Runx3 KO peripheral CD8 T cells also expressed CD4, and in contrast to wild-type, their proliferation ability was largely reduced. In addition, the in vitro cytotoxic activity of alloimmunized peritoneal exudate lymphocytes was significantly lower in Runx3 KO compared with WT mice. In a compound mutant mouse, null for Runx3 and heterozygous for Runx1 (Runx3 ؊/؊ ;Runx1 ؉/؊ ), all peripheral CD8 T cells also expressed CD4, resulting in a complete lack of single-positive CD8 ؉ T cells in the spleen. The results provide information on the role of Runx3 and Runx1 in thymopoiesis and suggest that both act as transcriptional repressors of CD4 expression during T cell lineage decisions.T he mammalian RUNX3͞AML2 gene resides on human chromosome 1p36.1 and mouse chromosome 4, respectively (1-4). It belongs to the RUNX family of transcription factors, which contains three genes. The two other family members, RUNX1 and RUNX2, play fundamental roles in hematopoietic and osteogenic lineage-specific gene expression, and when mutated, are associated with human diseases (5, 6). The three RUNX genes are regulated at the transcriptional level by two promoters, and at the translational level by internal ribosome entry site (IRES)-and cap-dependent translation control (7-14). The gene products of RUNX bind to the same DNA motif and activate or repress transcription of target genes through recruitment of common transcriptional modulators (15)(16)(17)(18). Despite this occurrence, each of the Runx genes has well defined biological functions reflected in a different expression pattern of the genes (19-23) and distinct phenotypes of the corresponding knockout mice (6,(24)(25)(26)(27).During mouse embryogenesis Runx3 is expressed in hematopoietic organs, epidermal appendages, developing bones, and sensory ganglia (20). Studies in knockout (KO) mice revealed that Runx3 is a neurogenic-specific transcription factor required for development and survival of TrkC neurons in the dorsal root ganglia. In the absence of Runx3 these neurons die, leading to disruption of the stretch reflex neuronal circuit, and consequently to severe ataxia (25,26). Intriguingly, in one strain of Runx3 KO, the gastric mucosa of newborn mice exhibits hyperplasia due to stimulated proliferation and suppressed apoptosis of stomach epithelial cells (27).It has previously been reporte...

Runx3 transcription factor regulates cell lineage decisions in thymopoiesis and neurogenesis. Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion. Runx3 is specifically expressed in mature dendritic cells (DC) and mediates their response to TGF-b. In the absence of Runx3, DC become insensitive to TGF-b-induced maturation inhibition, and TGF-b-dependent Langerhans cell development is impaired. Maturation of Runx3 KO DC is accelerated and accompanied by increased efficacy to stimulate T cells and aberrant expression of b2-integrins. Lung alveoli of Runx3 KO mice accumulate DC characteristic of allergic airway inflammation. Taken together, abnormalities in DC function and subset distribution may constitute the primary immune system defect, which leads to the eosinophilic lung inflammation in Runx3 KO mice. These data may help elucidate the molecular mechanisms underlying the pathogenesis of allergic airway inflammation in humans.

The human RUNX3/AML2 gene belongs to the 'runt domain' family of transcription factors that act as gene expression regulators in major developmental pathways. Here, we describe the expression pattern of Runx3 during mouse embryogenesis compared to the expression pattern of Runx1. E10.5 and E14.5-E16.5 embryos were analyzed using both immunohistochemistry and beta-galactosidase activity of targeted Runx3 and Runx1 loci. We found that Runx3 expression overlapped with that of Runx1 in the hematopoietic system, whereas in sensory ganglia, epidermal appendages, and developing skeletal elements, their expression was confined to different compartments. These data provide new insights into the function of Runx3 and Runx1 in organogenesis and support the possibility that cross-regulation between them plays a role in embryogenesis.