Biomedical subjects

W Kaelin

Publications and source records attributed to W Kaelin.

5 recordsLinked to original sources

PubMed2001

Human cytotrophoblast expression of the von Hippel-Lindau protein is downregulated during uterine invasion in situ and upregulated by hypoxia in vitro.

The von Hippel-Lindau tumor-suppressor protein (pVHL) regulates the stability of HIF1 alpha and HIF2 alpha and thus is pivotal in cellular responses to changes in oxygen tension. Paradoxically, human cytotrophoblasts proliferate under hypoxic conditions comparable to those measured in the early gestation placenta (2% O(2)), but differentiate into tumorlike invasive cells under well-oxygenated conditions such as those found in the uterus. We sought to explain this phenomenon in terms of pVHL expression. In situ, pVHL immunolocalized to villous cytotrophoblast stem cells, and expression was enhanced at sites of cell column initiation; in both of these relatively hypoxic locations, cytoplasmic staining for HIF2 alpha was also detected. As cytotrophoblasts attached to and invaded the uterus, which results in their increased exposure to oxygen, pVHL staining was abruptly downregulated concordant with localization of HIF2 alpha to the nucleus. In vitro, hypoxia (2% O(2)) upregulated cytotrophoblast pVHL expression together with HIF2 alpha, which localized to the cytoplasm; culture under well-oxygenated conditions greatly reduced levels of both molecules. These results, together with the placental defects previously observed in VHL(-/-) mice, suggest that pVHL is a component of the mechanism that transduces local differences in oxygen tension at the maternal-fetal interface to changes in the biological behavior of cytotrophoblasts. Furthermore, these data provide the first example of oxygen-dependent changes in pVHL abundance.

Basic Helix-Loop-Helix Proteins↗

PubMed1999

Third International Meeting on von Hippel-Lindau disease.

Five years after the identification of the von Hippel-Lindau (VHL) gene, physicians, scientists and concerned VHL family members met to review the current state of knowledge on the diagnosis and treatment of VHL and to summarize the latest information on the biochemistry of the VHL protein (pVHL). The NIH and University of Pennsylvania groups reported the detection of germ-line mutations in 100% (93 of 93) of VHL families studied. Several studies determined the frequency of VHL germ-line mutations in individuals with a single manifestation of VHL without a family history of VHL. National groups to improve the diagnosis and treatment of individuals with VHL disease have been established in Great Britain, Denmark, France, Holland, Italy, Japan, Poland, and the United States. Evidence for the existence of genes that modify the expression of VHL was presented. The VHL protein appears to have several distinct functions: (a) down-regulation of hypoxia-inducible mRNAs; (b) proper assembly of the extracellular fibronectin matrix; (c) regulation of exit from the cell cycle; and (d) regulation of expression of carbonic anhydrases 9 and 12.

Animals↗

PubMed1998

von Hippel-Lindau gene-mediated growth suppression and induction of differentiation in renal cell carcinoma cells grown as multicellular tumor spheroids.

Previous results using gene transfection methods have shown that the wild-type (WT) von Hippel-Lindau (VHL) gene can function as a potent tumor suppressor gene in vivo for renal cell carcinoma (RCC) cells in the absence of any suppressive effect on cell growth in monolayer cell culture under serum-rich conditions. Because we had previously found that the function of some oncogenes, such as mutant ras, can be influenced by three-dimensional growth as multicellular spheroids (J. Rak et aL, J. Cell Biol., 131: 1587-1598, 1995), we reasoned the same might be true for suppressor genes as well. We, therefore, decided to compare and study the effects of the WT VHL gene in monolayer versus three-dimensional culture systems of the RCC cell line 786-0, which contains an inactivated VHL gene. We found that the reintroduction of the WT VHL gene into mutant VHL RCC cells resulted in growth suppression in vitro, but only when the cells were grown as spheroid cultures. This decrease in cell proliferation was associated with several features of cell differentiation/morphogenesis, as shown by light and electron microscopy. Thus, in contrast to cultures of mutant VHL RCC cells, which formed very compact and cohesive spheroids, the WT VHL transfectants were loosely arranged and formed a network of tubular and trabecular structures within the spheroids. The morphological changes of the WT VHL spheroids were associated with the deposition of fibronectin in the extracellular space, a feature that was absent in the mutant and inactivated VHL gene-expressing spheroids. The results suggest the VHL gene may be involved in the maintenance of the epithelial phenotype of renal tubular cells, ie., it may act as a differentiation/morphogenetic factor. Moreover, this effect in tumors cells appears to be highly dependent on multicellular growth conditions that mimic the basic nature of solid tumors, such as RCC.

Animals↗

PubMed1993

Structural and functional contributions to the G1 blocking action of the retinoblastoma protein. (the 1992 Gordon Hamilton Fairley Memorial Lecture).

The retinoblastoma gene product (RB) contributes to normal cell growth control. One of its functions is manifest as a block to exit from G1, which is carried out by an RB subspecies which is un- or underphosphorylated. After RB phosphorylation, a process which occurs towards the end of G1 in cycling cells, the block is lifted allowing a cell to enter S. Here, we review a series of results which speak to the elements of RB structure which contribute to this activity. Included is its internal colinear protein receptor domain (i.e. the 'pocket').

Cell Division↗

PubMed1985

Lymphoscintigraphy.

Lymphoscintigraphy has been used as a noninvasive means of evaluating lymph node involvement. The potential exists for its wider application to other malignancies. Additionally, it is useful in determining the etiology of edema of the extremities. We report the use of 99mTc-antimony sulfide colloid lymphoscintigraphy to determine the etiology of edema of an extremity in a lymphoma patient.

Antimony↗