Cigarette Smoking Exacerbates Skeletal Muscle Injury without Compromising Its Regenerative Capacity.

Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease negatively impacts quality of life and survival. Cigarette smoking (CS) is the major risk factor for chronic obstructive pulmonary disease and skeletal muscle dysfunction; however, how CS affects skeletal muscle function remains enigmatic. To examine the impact of CS on skeletal muscle inflammation and regeneration, male BALB/c mice were exposed to CS for 8 weeks before muscle injury was induced by barium chloride injection, and were maintained on the CS protocol for up to 21 days after injury.

The human trithorax protein hASH2 functions as an oncoprotein.

Regulation of chromatin is an important aspect of controlling promoter activity and gene expression. Posttranslational modifications of core histones allow proteins associated with gene transcription to access chromatin. Closely associated with promoters of actively transcribed genes, trimethylation of histone H3 at lysine 4 (H3K4me3) is a core histone mark set by several protein complexes.

Oncogenic c-H-ras deregulates survivin expression: an improvement for survival.

Survivin protein accomplishes two basic functions: cell cycle regulation and control of apoptosis. It is only expressed in G2/M phase and it influences rescue pathways in apoptosis-induced cells. Overexpression of constitutive active c-H-ras in HeLa, or induction of c-H-ras in a stable HeLaDiR cell line, led to sustained survivin expression in all cell cycle phases and even protected cells from drug induced apoptosis.

Telomerase- and alternative telomere lengthening-independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT.

In the majority of human malignancies, maintenance of telomeres is achieved by reactivation of telomerase, whereas a smaller fraction uses an alternative telomere lengthening (ALT) mechanism. Here, we used 16 non-small cell lung cancer (NSCLC) cell lines to investigate telomere stabilization mechanisms and their effect on tumor aggressiveness. Three of 16 NSCLC cell lines (VL-9, SK-LU-1, and VL-7) lacked telomerase activity, correlating with significantly reduced tumorigenicity in vitro and in vivo.

Truncated ALK derived from chromosomal translocation t(2;5)(p23;q35) binds to the SH3 domain of p85-PI3K.

The chromosomal translocation t(2;5)(p23;q35) is associated with "Anaplastic large cell lymphomas" (ALCL), a Non Hodgkin Lymphoma occurring in childhood. The fusion of the tyrosine kinase gene-ALK (anaplastic lymphoma kinase) on chromosome 2p23 to the NPM (nucleophosmin/B23) gene on chromosome 5q35 results in a 80 kDa chimeric protein, which activates the "survival" kinase PI3K. However, the binding mechanism between truncated ALK and PI3K is poorly understood.

PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation.

The proto-oncoprotein c-Myc functions as a transcriptional regulator that controls different aspects of cell behavior, including proliferation, differentiation, and apoptosis. In addition, Myc proteins have the potential to transform cells and are deregulated in the majority of human cancers. Several Myc-interacting factors have been described that mediate part of Myc's functions in the control of cell behavior.

Caspase-9 plays a marginal role in serum starvation-induced apoptosis.

Serum withdrawal represents a potent trigger to induce caspase-dependent apoptosis in a series of cell culture models. In rat 423-cells, caspase-8 and caspase-3 were apparently sufficient to initiate and proceed apoptosis without involving the intrinsic amplification loop via caspase-9. To assess the reasons for this inactivity of an otherwise crucial initiator caspase, we examined the ability for apoptosome assembly in 423-cells.

bFGF rescues 423-cells from serum starvation-induced apoptosis downstream of activated caspase-3.

Serum withdrawal rapidly induces apoptosis in rat 423-cells, while addition of bFGF results in cell survival. However, surviving cells initially display morphological changes characteristic for apoptotic cells and even process caspases. Active caspase-3 was detected at the single-cell level in those finally bFGF-rescued cells, while mitochondrial integrity was maintained.

Subcellular localisation of Cdc25A determines cell fate.

Cell division cycle 25A (Cdc25A) was shown to colocalise both with nuclear and cytoplasmic proteins. Recently, we have demonstrated that overexpressed Cdc25A promoted the survival of rat 423 cells through indirect activation of PKB-protein kinase B. Using a Cdc25A:ER fusion protein, which can be shuttled from the cytoplasm into the nucleus, the present investigation evidences that the antiapoptotic effect of Cdc25A was restricted to its cytoplasmic localisation in rat 423 cells.

Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras.

Among the inhibitors of apoptosis proteins (IAPs), survivin has attracted special attention through its involvement in human cancer. The mechanism underlying tumour-associated survivin re-expression is not known. We found a correlation between exogenous c-H-Ras oncoprotein and endogenous survivin in a series of rat cell lines, which expressed defined oncogenes.

Repression of in vivo growth of Myc/Ras transformed tumor cells by Mad1.

The Myc/Max/Mad network of transcriptional regulatory proteins plays an essential role in cell proliferation, growth, apoptosis, and differentiation. Whereas Myc proteins affect cell cycle progression positively, Mad proteins are negative regulators of cell proliferation. It has been shown in several in vitro systems that Mad proteins antagonize c-Myc functions.

Cdc25A phosphatase suppresses apoptosis induced by serum deprivation.

The phosphatase Cdc25A was shown to be a target of the transcription factor c-Myc. Myc-induced apoptosis appeared dependent on Cdc25A expression and Cdc25A over-expression could substitute for Myc-triggered apoptosis. These findings suggested that an important downstream component of Myc-mediated apoptosis was identified.

Nuclear Ras: unexpected subcellular distribution of oncogenic forms.

The Harvey-ras gene encodes small guanine nucleotide binding proteins, mutant forms of which are associated with a number of human malignancies. Based on studies with truncated forms of the protein it is known that correct post-translational processing of Ras is essential for cytoplasmic membrane localization and function. Surprisingly, immunofluorescence analysis provided evidence that in addition to its cytosolic localization, activated H-Ras(Val 12) was also localized in the nuclei of transformed cells both in vitro and in vivo.

Targeted inhibition of telomerase in human cancer: will it be a double-edged sword?

More than 80% of human malignancies express telomerase activity, while normal somatic tissues in general lack it. During each normal cell division, there is a constant loss of DNA sequences at chromosomal ends, which is due to the 'end-replication problem' of conventional DNA polymerase. Critical shortening of telomeres induces cell cycle arrest and eventually cell death.

Telomeres, telomerase, and myc. An update.

Normal human somatic cells have a finite life span in vivo as well as in vitro and retire into senescence after a predictable time. Cellular senescence is triggered by the activation of two interdependent mechanisms. One induces irreversible cell cycle exit involving activation of two tumorsuppressor genes, p53 and pRb, and the proper time point is indicated by a critical shortening of chromosomal ends due to the end-replication problem of DNA synthesis.

Modulation of invasive properties of murine squamous carcinoma cells by heterologous expression of cathepsin B and cystatin C.

Murine SCC-VII squamous carcinoma cells have the capacity to penetrate reconstituted basement membranes (Matrigel) in vitro. The invasion of Matrigel layers by SCC-VII cells was significantly reduced by E-64, a specific inhibitor of lysosomal cysteine proteinases. The cathepsin-B-selective E-64 derivative, CA-074, inhibited penetration of Matrigel by SCC-VII cells to the same extent, indicating a major role for this particular lysosomal enzyme in extracellular-matrix degradation during squamous-carcinoma-cell invasion.

YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of YY1 but neither its transactivation domain nor direct interaction with c-Myc.

The proto-oncoprotein c-Myc and the multifunctional transcriptional regulator YY1 have been shown previously to interact directly in a manner that excludes Max from the complex (Shrivastava et al., 1993). As binding to Max is necessary for all known c-Myc activities we have analysed the influence of YY1 on c-Myc function.

Expression of mouse RNase MRP RNA in human embryonic kidney 293 cells.

We report on the expression of mouse RNase MRP RNA in human embryonic kidney 293 cells upon DNA transfection. Stable cell lines were selected by cotransfection with a neor gene. Transcription of wild-type and deletion mutants of MRP RNA and ribonucleoprotein formation were assessed by RNase protection and immunoprecipitation experiments.

Oxidized low-density-lipoprotein triggers programmed death of endothelial cells.

Incubation of bovine aortic as well as human umbilical vein endothelial cells with either oxidized or native low-density-lipoprotein in the presence of trace amounts of copper induced morphological changes of the cells and chromatin fragmentation characteristic for programmed cell death. Shrinkage of cells was evident after 6 to 8 hours of incubation and clearly preceded release of lactate dehydrogenase as a marker of cell permeability. Condensation of nuclear chromatin and internucleosomal cleavage was demonstrated by Hoechst staining and gel electrophoresis, respectively.