Runx proteins are involved in regulation of CD122, Ly49 family and IFN-gamma expression during NK cell differentiation.
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Runx family proteins play indispensable roles in the development of various hematopoietic lineage cells. However, their function in NK cells is still uncertain. We found that NK cells and CD8 T cells dominantly express Runx3 protein, whereas NKT cells and CD4 T cells express Runx1. Reverse transcription-PCR analysis revealed that Runx3 expression is initiated at the NK precursor stage and is maintained along the course of NK cell differentiation. In order to examine their role in the earlier stage of NK cell development, we introduced Runx dominant-negative (Runx dn) form into Lin(-)c-kit(+)Sca-1(+) hematopoietic stem cells, which were applied to NK cell-inducing culture. Post-cultured cells showed a decreased expression of IL-2/IL-15 common receptor beta subunit (CD122), consistent with another finding that Runx binds to promoter region of CD122 gene. To examine the Runx function in the later developmental stage, we used transgenic mouse, in which Runx dn form is expressed in immature and mature NK cells. This mouse showed decreased expressions of NK maturation markers, such as Ly49 family, Mac-1 and CD43, whereas IFN-gamma production was greatly enhanced. These findings suggest that Runx proteins, especially Runx3, play multiple roles in NK cell differentiation. (+info)
Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on 3 sites increases transactivation potency and stimulates cell proliferation.
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RUNX1/AML1 regulates lineage-specific genes during hematopoiesis and stimulates G1 cell-cycle progression. Within RUNX1, S48, S303, and S424 fit the cyclin-dependent kinase (cdk) phosphorylation consensus, (S/T)PX(R/K). Phosphorylation of RUNX1 by cdks on serine 303 was shown to mediate destabilization of RUNX1 in G2/M. We now use an in vitro kinase assay, phosphopeptide-specific antiserum, and the cdk inhibitor roscovitine to demonstrate that S48 and S424 are also phosphorylated by cdk1 or cdk6 in hematopoietic cells. S48 phosphorylation of RUNX1 paralleled total RUNX1 levels during cell-cycle progression, S303 was more effectively phosphorylated in G2/M, and S424 in G1. Single, double, and triple mutation of the cdk sites to the partially phosphomimetic aspartic acid mildly reduced DNA affinity while progressively increasing transactivation of a model reporter. Mutation to alanine increased DNA affinity, suggesting that in other gene or cellular contexts phosphorylation of RUNX1 by cdks may reduce transactivation. The tripleD RUNX1 mutant rescued Ba/F3 cells from inhibition of proliferation by CBFbeta-SMMHC more effectively than the tripleA mutant. Together these findings indicate that cdk phosphorylation of RUNX1 potentially couples stem/progenitor proliferation and lineage progression. (+info)
Runx genes are direct targets of Scl/Tal1 in the yolk sac and fetal liver.
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CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci.
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RUNX3 inhibits growth of HCC cells and HCC xenografts in mice in combination with adriamycin.
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Here, we report that a loss or decrease of RUNX3 expression was found in 73 cases of HCCs as compared with that in normal liver tissues (p < 0.001). Various human HCC cell lines also exhibited loss or decrease of RUNX3 expression. The introduction of RUNX3 by an adenovirus vector into HCC cell lines which had decreased expressions of RUNX3 inhibited cell proliferation and cell cycle progression, decreased anchorage-independent growth, and inhibited tumorigenesis in nude mice. Exogenous expression of RUNX3 sensitized HCC cells to cytotoxic drugs and to apoptosis induced by chemotherapeutic drug adriamycin in vitro. Ectopic expression of RUNX3 in HCC cells enhanced caspase-8 and decreased Bcl-2 expression. Treatment of nude mice bearing subcutaneously established HCC tumors with a combination of an adenovirus expressing RUNX3 and adriamycin completely suppressed tumor growth. In conclusion, overexpression of RUNX3 might be a promising candidate as a treatment for HCC that would increase sensitivity to chemotherapeutic drugs. (+info)
Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung.
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