Kari Alitalo

Bio: Kari Alitalo is an academic researcher from University of Helsinki. The author has contributed to research in topics: Angiogenesis & Vascular endothelial growth factor C. The author has an hindex of 174, co-authored 817 publications receiving 114231 citations. Previous affiliations of Kari Alitalo include Mount Sinai Hospital, Toronto & Cornell University.

Extracellular matrix proteins of human epidermal keratinocytes and feeder 3T3 cells.

Abstract: Cultures of human epidermal keratinocytes obtained from adult epidermis were initiated using irradiated BALB/3T3 cells as feeder layers. At different stages of confluence of the epidermal islands, feeder cells were removed and the extracellular matrix proteins of both pure component cells and cocultures were analyzed biochemically and by immunochemical methods and compared to those of skin fibroblasts of the same donors. The keratinocytes synthesized and secreted fibronectin and small amounts of laminin and type IV collagen. In addition, a nondisulfide-linked collagenous polypeptide (Mr = 120,000) was synthesized by the keratinocytes and was confined to the cell layers. Collagenous polypeptides with Mr = 120,000 were also synthesized by organ cultures of epidermal tissue and were detected in its acid or detergent extracts but again no secretion to culture medium was found. The Mr = 120,000 collagen had biochemical and immunological properties distinct from those of types I-V collagens. In immunofluorescence of keratinocyte cultures, fibronectin staining was prominent in the lining marginal cells of the expanding periphery of the epidermal cell islands but was not detected in the terminally differentiating cells in the upper layers of stratified colonies. Very little type IV collagen was found deposited in pericellular matrix form by the keratinocytes. In contrast, the mouse 3T3 feeder cells were found to produce both type IV collagen and laminin in addition to the previously identified connective tissue glycoproteins of fibroblasts, interstitial procollagens, and fibronectin. Basement membrane collagen of the 3T3 cells was found deposited as apparently unprocessed procollagen alpha 1(IV) and alpha 2(IV) chains. The production in culture conditions of basal lamina glycoproteins by the fibroblastic feeder cells may promote the attachment and growth of the cocultured keratinocytes.

c-Myc induces cellular susceptibility to the cytotoxic action of TNF-alpha.

Abstract: Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine which is cytotoxic for some tumor cells and transformed cells. The molecular mechanisms which render transformed and tumor cells sensitive to the cytotoxic action of TNF are unclear. We show here that an increased expression of the c-Myc oncoprotein strongly increases cellular sensitivity to TNF cytotoxicity. In Rat1A fibroblasts, which are resistant to TNF, the addition of TNF with a concomitant activation of a hormone-inducible c-Myc-estrogen receptor chimera (MycER) resulted in apoptotic cell death. Similarly, c-Myc overexpression enhanced the sensitivity of NIH3T3 fibroblasts to TNF-induced death. The c-Myc and TNF-induced apoptosis was inhibited by ectopic expression of the Bcl2 oncoprotein and by the free oxygen radical scavenging enzyme Mn superoxide dismutase. Furthermore, in highly TNF-sensitive fibrosarcoma cells, antisense c-myc oligodeoxynucleotides caused a specific inhibition of TNF cytotoxicity. Our results suggest that the deregulation of c-Myc, which is common in human tumors and tumor cell lines is one reason why these cells are TNF sensitive.

Nucleotide sequence to the v-myc oncogene of avian retrovirus MC29

Abstract: Avian myelocytomatosis viruses are retroviruses whose oncogene (v-myc) induces an unusually wide variety of tumors, including carcinomas, endotheliomas, sarcomas, and myelocytomatoses. The viral gene v-myc arose by transduction of an undetermined portion of a cellular gene known as c-myc. In order to facilitate further studies of the functions of v-myc and c-myc and to permit detailed comparisons between the two genes, we have determined the nucleotide sequence of v-myc in the genome of the MC29 strain of myelocytomatosis virus. The v-myc domain in MC29 virus encodes a hydrophilic polypeptide with a molecular weight of 47,000, fused to a portion of the polyprotein encoded by the viral structural gene gag. The carboxyl-terminal half of the v-myc polypeptide is rich in basic amino acid residues. This feature may account for the DNA-binding properties of the hybrid gag-myc-encoded protein which would have a molecular weight of approximately 100,000, in accord with results from previous studies of the protein encoded by v-myc. The junctions between v-myc and the genome of the transducing virus are apparent but reveal no clues to the mechanism by which transduction might occur.

Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response.

Abstract: Endothelial receptor tyrosine kinases (RTKs) and their signaling mechanisms are of interest because they may control tumor angiogenesis and thereby tumor growth In this report we have examined activation of the signal transducers and activators of transcription (STATs) by the three known vascular endothelial growth factor receptors (VEGFR1-3), as well as by the endothelial Tie-1 and -2 receptors We also studied signaling by the R849W mutant of Tie-2 (MTie-2), which has been shown to cause venous malformations When overexpressed in 293T cells, MTie-2 activated STAT1 while the other endothelial RTKs failed to do so In contrast, the three VEGFRs were strong activators of STAT3 and STAT5, suggesting that they activate only a specific subset of these signal transducers STAT3 and STAT5 were also activated by Tie-2 and, more so, by MTie-2 Tyrosine phosphorylation and DNA binding of STATs correlated with their ability to activate transcription as judged by luciferase assays When co-expressed with STAT5, VEGFR-1 as well as both the Tie-2 receptor forms increased expression of the cell cycle inhibitor p21 Interestingly, co-expression of the Tie-2 receptors with STAT1 resulted in appearance of a novel, p21 related transcript Taken together, these findings identify STAT proteins as novel targets for signal transduction by the endothelial RTKs, suggesting that they may be involved in the regulation of endothelial function

Intravascular Adenovirus-Mediated VEGF-C Gene Transfer Reduces Neointima Formation in Balloon-Denuded Rabbit Aorta

Abstract: Background—Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with lacZ adenovirus. Clinical-grade adenoviruses were used for the study. Methods and Results—Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the lacZ-transfected control group was 0.5760.04. VEGF-C gene transfer reduced I/M to 0.3860.02 (P,0.05 versus lacZ group). I/M in VEGF-A‐treated animals was 0.4960.17 (P5NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the lacZ group had an I/M of 0.7360.16, the VEGF-C group 0.4460.14, and the VEGF-A group 0.6360.21 (P5NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between lacZ adenovirus and 0.9% saline‐treated animals. Conclusions—Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations. (Circulation. 2000;102:2262-2268.)

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Inflammation and cancer

Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Abstract: The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.