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Barbara Munz

Publications and source records attributed to Barbara Munz.

5 recordsLinked to original sources
PubMed2006

Regulation of NF-kappaB activity and keratinocyte differentiation by the RIP4 protein: implications for cutaneous wound repair.

Receptor-interacting proteins (RIPs) are important regulators of cell proliferation and differentiation. As RIP4 is a crucial modulator of epidermal differentiation, we analyzed the expression of different rip genes in healing skin wounds. Rip4 expression was strongly downregulated in keratinocytes of the hyperproliferative epithelium at the wound edge early after injury and only returned to basal levels after completion of wound repair. Rip3 expression was strongly induced as early as 1 day after wounding. In contrast, rip and rip2 expression remained unaltered. To determine the factors that regulate rip4 gene expression in keratinocytes, human HaCaT keratinocytes were used as a model system. We found that scratch wounding as well as treatment with whole serum, phorbol esters, the growth/differentiation factors epidermal growth factor, transforming growth factor-beta, and activin A, or the proinflammatory cytokines tumor necrosis factor-alpha and IL-1beta strongly suppressed rip4 expression in these cells. In contrast, the steroid dexamethasone and all-trans retinoic acid slightly stimulated rip4 expression. Suppression of rip4 expression in keratinocytes using small interfering RNA technology reduced the activation of NF-kappaB, and enhanced the expression of epidermal differentiation markers in these cells. These data suggest important and unique functions of different RIP proteins in keratinocytes of normal and wounded skin.

Animals↗
PubMed2006

Differential expression of entactin-1/nidogen-1 and entactin-2/nidogen-2 in myogenic differentiation.

Here, we show that entactin-2 expression is strongly, but transiently, induced in myogenic differentiation. Treatment of C2C12 myoblasts with actinomycin D in parallel to the induction of differentiation could demonstrate that this is due to enhanced transcription of the entactin-2 gene. Furthermore, treatment with the translation inhibitor cycloheximide could show that entactin-2 is a primary response gene. As p38 MAP kinase is an important regulator of myogenic differentiation, we also analyzed the possibility that entactin-2 might be a target of this pathway. However, using various p38 MAPK inhibitors, we could not detect involvement of p38 in entactin-2 up-regulation. Most remarkably, expression of the entactin-2 homolog entactin-1 dramatically declined in myogenesis, suggesting different functions of the two entactins in this process. A similar effect was seen in primary myoblasts isolated from two different mouse strains. Expression of high levels of entactin-1 in myoblasts using a retroviral expression system led to a higher proliferation rate both in growth and in differentiation medium and to reduced expression of various myogenic differentiation markers after the induction of differentiation. Furthermore, decreased expression of the entactin-2 gene after treatment of the cells with ent-2-specific siRNA preparation led to reduced expression of the cell cycle inhibitor p21. These data suggest important and distinct functions of entactin-1 and -2 in myogenic differentiation.

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PubMed2002

The PreS2 activator MHBs(t) of hepatitis B virus activates c-raf-1/Erk2 signaling in transgenic mice.

The large hepatitis B virus (HBV) surface protein (LHBs) and C-terminally truncated middle size surface proteins (MHBs(t)) form the family of the PreS2 activator proteins of HBV. Their transcriptional activator function is based on the cytoplasmic orientation of the PreS2 domain. MHBs(t) activators are paradigmatic for this class of activators. Here we report that MHBs(t) is protein kinase C (PKC)-dependently phosphorylated at Ser28. The integrity of the phosphorylation site is essential for the activator function. MHBs(t) triggers PKC-dependent activation of c-Raf-1/Erk2 signaling that is a prerequisite for MHBs(t)-dependent activation of AP-1 and NF-kappaB. To analyze the pathophysiological relevance of these data in vivo, transgenic mice were established that produce the PreS2 activator MHBs(t) specifically in the liver. In these mice, a permanent PreS2-dependent specific activation of c-Raf-1/Erk2 signaling was observed, resulting in an increased hepatocyte proliferation rate. In transgenics older than 15 months, an increased incidence of liver tumors occurs. These data suggest that PreS2 activators LHBs and MHBs(t) exert a tumor promoter-like function by activation of key enzymes of proliferation control.

Amino Acid Sequence↗
PubMed2002

RIP2, a checkpoint in myogenic differentiation.

Using a subtractive cDNA library hybridization approach, we found that receptor interacting protein 2 (RIP2), a tumor necrosis factor receptor 1 (TNFR-1)-associated factor, is a novel early-acting gene that decreases markedly in expression during myogenic differentiation. RIP2 consists of three domains: an amino-terminal kinase domain, an intermediate domain, and a carboxy-terminal caspase activation and recruitment domain (CARD). In some cell types, RIP2 has been shown to be a potent inducer of apoptosis and an activator of NF-kappa B. To analyze the function of RIP2 during differentiation, we transduced C2C12 myoblasts with retroviral vectors to constitutively produce RIP2 at high levels. When cultured in growth medium, these cells did not show an enhanced rate of proliferation compared to controls. When switched to differentiation medium, however, they continued to proliferate, whereas control cells withdrew from the cell cycle, showed increased expression of differentiation markers such as myogenin, and began to differentiate into multinucleated myotubes. The complete RIP2 protein appeared to be necessary to inhibit myogenic differentiation, since two different deletion mutants lacking either the amino-terminal kinase domain or the carboxy-terminal CARD had no effect. A mutant deficient in kinase activity, however, had effects similar to wild-type RIP2, indicating that phosphorylation was not essential to the function of RIP2. Furthermore, RIP proteins appeared to be important during myogenic differentiation in vivo, as we detected a marked decrease in expression of the RIP2 homolog RIP in several muscle tissues of the dystrophic mdx mouse, a model for continuous muscle degeneration and regeneration. We conclude that RIP proteins can act independently of TNFR-1 stimulation by ligand to modulate downstream signaling pathways, such as activation of NF-kappa B. These results implicate RIP2 in a previously unrecognized role: a checkpoint for myogenic proliferation and differentiation.

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