Biomedical subjects

Sue J Sohn

Publications and source records attributed to Sue J Sohn.

4 recordsLinked to original sources

PubMed2005

Transcriptional regulation of tissue-specific genes by the ERK5 mitogen-activated protein kinase.

The ERK5 mitogen-activated protein kinase (MAPK) differs from other MAPKs in possessing a potent transcriptional activation domain. ERK5-/- embryos die from angiogenic defects, but the precise physiological role of ERK5 remains poorly understood. To elucidate molecular functions of ERK5 in the development of vasculature and other tissues, we performed gene profile analyses of erk5-/- mouse embryos and erk5-/- fibroblast cells reconstituted with ERK5 or ERK5(1-740), which lacks the transactivation domain. These experiments revealed several potential ERK5 target genes, including a proapoptotic gene bnip3, known angiogenic genes flt1 and lklf (lung Krüppel-like factor), and genes that regulate cardiovascular development. Among these, LKLF, known for its roles in angiogenesis, T-cell quiescence, and survival, was found to be absolutely dependent on ERK5 for expression in endothelial and T cells. We show that ERK5 drives lklf transcription by activating MEF2 transcription factors. Expression of erk5 short hairpin or a dominant-negative form of the ERK5 upstream activator, MEK5, in T cells led to downregulation of LKLF, increased cell size and upregulation of activation markers. Thus, through its kinase and transcriptional activation domains, ERK5 regulates transcriptional responses of cell survival and quiescence critical for angiogenesis and T-cell function.

Amino Acid Motifs↗

PubMed2003

Apoptosis during lymphoid development.

Recent investigations have provided important insights into how signaling through the antigen receptors determines whether a cell survives or dies. In T cells, Grb2 and MAP kinases play essential roles in differentiating between apoptotic and survival signals. The PTEN phosphatase and Bim, a pro-apoptotic Bcl-2 family member, regulate apoptosis in both T and B cells. In B cells, antigen receptor-mediated death can be rescued by co-stimulation, in which the roles of protein kinase C and BAFF, a TNF family member, have been recently elucidated. In a recently identified mechanism of regulating inflammation, receptors such as c-mer and glycoproteins such as MFG-E8 were found to participate in the clearance of apoptotic cells.

Animals↗

PubMed2003

A function of Fas-associated death domain protein in cell cycle progression localized to a single amino acid at its C-terminal region.

FADD is an adaptor known to transmit apoptotic signals from members of the tumor necrosis factor receptor family. We show here that FADD has a domain implicated in cell proliferation. Mice bearing the Asp mutation in the serine 191 phosphorylation site are runted and anemic and display splenomegaly. Apoptosis is unimpaired in these mice, but they exhibit many immune developmental problems indicative of proliferative defects. Mutant FADD T cells are defective in cell cycle progression, suggesting that regulation of phosphorylation at serine 191 is essential for growth/proliferation. Remarkably, serine 191 is conserved among mammalian FADD proteins, but this C-terminal region is absent in lower organisms, suggesting that FADD acquired a domain during evolution, rendering it a "proliferation-apoptosis coupler" that balances cell proliferation and apoptosis.

Adaptor Proteins, Signal Transducing↗

PubMed2002

ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression.

During angiogenesis, endothelial cells undergo proliferation, reorganization, and stabilization to establish a mature vascular network. This process is critical for establishing a functional circulatory system during development and contributes to the pathological process of tumor growth. Here we report that embryos deficient for the ERK5 MAPK die between embryonic days 10.5 and 11.5 with angiogenic failure and cardiovascular defects. We show that ERK5 deficiency leads to an increased expression of the vascular endothelial growth factor (VEGF), dysregulation of which has been shown to impede angiogenic remodeling and vascular stabilization. Our data also reveal that ERK5 negatively regulates transcription from the vegf locus during hypoxic responses. Importantly, ERK5 is required at an earlier developmental stage than p38alpha, and p38alpha does not compensate for ERK5 deficiency. These results demonstrate that ERK5 plays a specific role in the regulation of early angiogenesis.

Animals↗