Biomedical subjects

Katya Ravid

Publications and source records attributed to Katya Ravid.

21 records · Page 2Linked to original sources

PubMed2002

Signaling by the Mpl receptor involves IKK and NF-kappaB.

Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor activates IKK complex, which leads to inducement of NF-kappaB activity. Here we report that activation of Mpl ligand is also linked to IKK and NF-kappaB activity. Mpl ligand, also known as thrombopoietin (TPO) or megakaryocyte growth and development factor (MGDF), induces megakaryocyte differentiation and inhibition of mitotic proliferation, followed by induction of polyploidization and fragmentation into platelets. The latter process is often observed in megakaryocytes undergoing apoptosis. Treatment of a Mpl ligand-responding megakaryocytic cell line with this cytokine led to an immediate, transient increase in IKK activity followed by a profound decrease in this kinase activity over time. This decrease was not due to an effect on the levels of the IKK regulatory components IKKalpha and IKKbeta. Proliferating megakaryocytes displayed a constitutive DNA-binding activity of NF-kappaB p50 homodimers and of NF-kappaB p50-p65 heterodimers. As expected, reduced IKK activity in Mpl ligand-treated cells was associated with a significant reduction in NF-kappaB DNA binding activity and in the activity of a NF-kappaB-dependent promoter. Our study is thus the first to identify a constitutive NF-kappaB activity in proliferating megakaryocytes as well as to describe a link between Mpl receptor signaling and IKK and NF-kappaB activities. Since a variety of proliferation-promoting genes and anti-apoptotic mechanisms are activated by NF-kappaB, retaining its low levels would be one potential mechanism by which inhibition of mitotic proliferation is maintained and apoptosis is promoted during late megakaryopoiesis.

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PubMed2002

Roads to polyploidy: the megakaryocyte example.

Polyploidy, recognized by multiple copies of the haploid chromosome number, has been described in plants, insects, and in mammalian cells such as, the platelet precursors, the megakaryocytes. Several of these cell types reach high ploidy via a different cell cycle. Megakaryocytes undergo an endomitotic cell cycle, which consists of an S phase interrupted by a gap, during which the cells enter mitosis but skip anaphase B and cytokinesis. Here, we review the mechanisms that lead to this cell cycle and to polyploidy in megakaryocytes, while also comparing them to those described for other systems in which high ploidy is achieved. Overall, polyploidy is associated with an orchestrated change in expression of several genes, of which, some may be a result of high ploidy and hence a determinant of a new cell physiology, while others are inducers of polyploidization. Future studies will aim to further explore these two groups of genes.

Animals↗

PubMed2002

Overexpression of A3 adenosine receptors in smooth, cardiac, and skeletal muscle is lethal to embryos.

The profile of expression of the A3 adenosine receptor (A3AR) and its importance during embryo development were explored. To this end, different ages of mouse embryos (8.5 days and older) were subjected to in situ hybridization with an A3AR riboprobe. No expression was found in any embryonic tissue except for the aorta and heart of 15.5-day embryos. To investigate further the role of the A3AR gene in development, we overexpressed this gene in A3AR knockout and wild-type mice by using the SM22 alpha promoter. This promoter is active in smooth, cardiac, and skeletal muscle lineages during early embryogenesis (at 8.5 days or earlier), becoming restricted to vascular and visceral smooth muscle cells in late fetal development and adult mice. We observed that moderate copy number incorporation (four copies) of the A3AR gene driven by the SM22 alpha promoter is sufficient to induce lethality at an early stage of embryo development. Remains of 8.5-day transgenic embryos were collected, including fragmented DNA. Hence, we speculate that A3AR homeostasis is critical for embryo viability and proper development. This finding is intriguing in view of the reported effects of sustained activation of the A3AR on induction of DNA fragmentation and apoptosis in cultured myocytes and other cell types.

Animals↗