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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.06.013 Byline: Sanjeev Das (1), Lakshmi Raj (1), Bo Zhao (2), Yuki Kimura (3), Alan Bernstein (3), Stuart A. Aaronson (2), Sam W. Lee (1) Keywords: CELLCYCLE; DNA; SIGNALING Abstract: A critical unresolved issue about the genotoxic stress response is how the resulting activation of the p53 tumor suppressor can lead either to cell-cycle arrest and DNA repair or to apoptosis. We show here that hematopoietic zinc finger (Hzf), a zinc-finger-containing p53 target gene, modulates p53 transactivation functions in an autoregulatory feedback loop. Hzf is induced by p53 and binds to its DNA-binding domain, resulting in preferential transactivation of proarrest p53 target genes over its proapoptotic target genes. Thus, p53 activation results in cell-cycle arrest in Hzf wild-type MEFs, while in Hzf.sup.-/- MEFs, apoptosis is induced. Exposure of Hzf null mice to ionizing radiation resulted in enhanced apoptosis in several organs, as compared to in wild-type mice. These findings provide novel insights into the regulation of p53 transactivation function and suggest that Hzf functions as a key player in regulating cell fate decisions in response to genotoxic stress. Author Affiliation: (1) Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA (2) Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA (3) Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G IX5, Canada Article History: Received 5 February 2007; Revised 1 May 2007; Accepted 5 June 2007 Article Note: (miscellaneous) Published: August 23, 2007

Germ-line mutations in the human BRCA2 gene confer susceptibility to breast cancer. Efforts to elucidate its function have revealed a putative transcriptional activation domain and in vitro interaction with the DNA repair protein RAD51. Other studies have indicated that RAD51 physically associates with the p53 tumor suppressor protein. Here we show that the BRCA2 gene product is a 460-kDa nuclear phosphoprotein, which forms in vivo complexes with both p53 and RAD51. Moreover, exogenous BRCA2 expression in cancer cells inhibits p53's transcriptional activity, and RAD51 coexpression enhances BRCA2's inhibitory effects. These findings demonstrate that BRCA2 physically and functionally interacts with two key components of cell cycle control and DNA repair pathways. Thus, BRCA2 likely participates with p53 and RAD51 in maintaining genome integrity.

Transfection processes and cDNA clones from an ovarian carcinoma cell line help detect a human oncogene TC21 that belongs to the RAS gene superfamily. Single point mutation and replacement of leucine with glutamine stimulates transforming activities in the oncogene. Unlike the cDNA clone, the ovarian tumor genomic DNA expressing TC21 allele mutations do not stimulate transforming activities.

An analysis of the expression constructs of cDNAs encoding individual immunoglobulin-like domains of the keratinocyte growth factor (KGF), revealed that the key binding regions for associated FGF ligands are localized to different immunoglobulin-like domains. The study involved the fusing of fibroblast growth factor (FGF)-7 receptor with the mouse immunoglobulin heavy chain Fe domain. Scatchard studies indicated that the chimera containing immunoglobulin-like domains 2 and 3 binds KGF and acidic FGF.

The function of interaction reactions in platelet-derived growth factor (PDGF) ligand mechanisms was examined. Reactions between two chains affect the discharge of PDGF. PDGF R attachment and stimulation are influenced by the interchain reactions as revealed by partial recovery by dimer production with a wild-type PDGF A chain of injured PDGF B mutant chain mechanism.

HGF WAS INITIALLY DETECTED AS A hormone-like activity capable of stimulating hepatocyte proliferation [1]. This growth factor is expressed by stromal fibroblasts and is mitogenic for a variety of cell [...]

Molecular Localization of the Transforming and Secretory Properties of PDGF A and PDGF B HUMAN PLATELET-DERIVED GROWTH factor (PDGF) is a major mitogen for cells of connective tissue origin that [...]

EGF Receptor and erbB-2 Tyrosine Kinase Domains Confer Cell Specificity for Mitogenic Signaling THE INTERACTION OF GROWTH FACTORS with specific membrane receptors triggers a series of intracellular events that are [...]