Biomedical subjects

Alex Lash

Publications and source records attributed to Alex Lash.

3 recordsLinked to original sources

PubMed2006

A FoxO-Smad synexpression group in human keratinocytes.

Transforming growth factor beta (TGF-beta) signals through activation of Smad transcription factors. Activated Smad proteins associate with different DNA-binding cofactors for the recognition and regulation of specific target genes. Members of the forkhead box O family (FoxO1, FoxO3, and FoxO4) play such a role in the induction of the cyclin-dependent kinase inhibitors p15Ink4b and p21Cip1. To delineate the organization of the TGF-beta response in human keratinocytes, we defined the set of genes whose activation by TGF-beta requires both FoxO and Smad functions. FoxO factors are shown to be essential for 11 of the 115 immediate gene activation responses to TGF-beta in these cells. FoxO1, FoxO3, and FoxO4 act redundantly as mediators of these effects. Smad4, which functions as a partner of receptor-phosphorylated Smad2/3, is required for all of these responses. These results define a FoxO-Smad synexpression group or group of genes that are jointly induced by a common mechanism in response to TGF-beta. In addition to p15INK4b and p21CIP1, these genes include mediators of stress responses (GADD45A, GADD45B, and IER1) and adaptive cell signaling responses (CTGF, JAG1, LEMD3, SGK, CDC42EP3, and OVOL1). Bioinformatic analysis of the promoter region of these genes reveals diverse configurations of Smad and FoxO binding elements, implying differences in the regulatory properties of this group of genes. Indeed, a subset of FoxO/Smad-dependent TGF-beta gene responses additionally require the transcription factor CCAAT/enhancer-binding protein beta. The composition of the FoxO-Smad synexpression group suggests that stress reactions and adaptive functions accompany the cytostatic response of keratinocytes to TGF-beta.

Binding Sites↗

PubMed2005

Frequent mutation of the PIK3CA gene in ovarian and breast cancers.

PURPOSE: Activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, resulting in increased cell proliferation, survival, and motility, is believed to play an oncogenic role in many cancer types. The PIK3CA gene encodes the p110alpha catalytic subunit of PI3K, and is amplified in some ovarian cancers, whereas the AKT2 gene is amplified in some ovarian, breast, and pancreatic cancers. Recently, in a mutational screen of eight PI3K genes and eight PI3K-like genes, PIK3CA was found to be the only gene affected by somatic mutations, which were observed frequently in gastrointestinal and brain cancers. Here, we test whether PIK3CA is subject to mutation in ovarian and breast cancers. EXPERIMENTAL DESIGN: Exons 9 and 20, encoding the highly conserved helical and kinase domains of PIK3CA, were subjected to sequence analysis in 198 advanced stage epithelial ovarian carcinomas and 72 invasive breast carcinomas (48 of ductal histology and 24 of lobular histology). RESULTS: Somatic missense mutations were observed in 24 of 198 (12%) ovarian carcinomas, and in 13 of 72 (18%) breast carcinomas. CONCLUSIONS: These data indicate that mutations of PIK3CA play an oncogenic role in substantial fractions of ovarian and breast carcinomas, and in consideration of mutation of other components of the PI3K-AKT pathway in both tumor types, confirm the major oncogenic role of this pathway in ovarian and breast carcinomas.

Base Sequence↗

PubMed2004

FlyGEM, a full transcriptome array platform for the Drosophila community.

We have constructed a DNA microarray to monitor expression of predicted genes in Drosophila. By using homotypic hybridizations, we show that the array performs reproducibly, that dye effects are minimal, and that array results agree with systematic northern blotting. The array gene list has been extensively annotated and linked-out to other databases. Incyte and the NIH have made the platform available to the community via academic microarray facilities selected by an NIH committee.

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