PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes

Abstract

Exposure of mammalian cells to hypoxia, radiation and certain chemotherapeutic agents promotes cell cycle arrest and/or apoptosis. Activation of p53 responsive genes is believed to play an important role in mediating such responses. In this study we identi®ed a novel gene, PA26, which maps to chromosome 6q21 and encodes at least three transcript isoforms, of which two are dierentially induced by genotoxic stress (UV, girradiation and cytotoxic drugs) in a p53-dependent manner. A functional p53-responsive element was identi®ed in the second intron of the PA26 gene, in consistence with a mechanism of transcriptional induction of the PA26 gene by p53. No clues to its functions were revealed by sequence analysis, although pronounced negative regulation by serum factors argues for a potential role of PA26 in growth regulation. Immunological analysis suggests that PA26 protein(s) is localized to the cell nucleus. Our results suggest that the PA26 gene is a novel p53 target gene with properties common to the GADD family of growth arrest and DNA damageinducible stress-response genes, and, thus, a potential novel regulator of cellular growth.

Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells

“…While this may explain the high basal expression of SESN1 as shown here in the absence of androgen, a mechanism as to why AR-siRNA reduced these levels remains elusive and the subject of further investigation ongoing in our lab. Induction of SESN1 follows similar trends to other known p53-regulated genes with increases occurring with cell cycle arrest (Velasco-Miguel et al, 1999). Thus, decreased proliferation of prostate cancer cells in response to castration would be expected to be associated with increased levels of SESN1 as observed here.…”

The Peroxiredoxin Repair Proteins

“…In Arabidopsis both the typical 2-Cys Prx and Srx are located in the chloroplast (Dietz et al, 2006;Liu et al, 2006). Northern blot analysis suggests that sestrin 1 is widely expressed in human tissues (Velasco-Miguel et al, 1999). In this study the highest mRNA levels were seen in skeletal muscles.…”

“…The sestrins are ∼48-60 kDa in size and show no sequence homology to the Srx family. The sestrins were originally discovered through subtractive cDNA cloning experiments designed to identify targets of the p53 protein (Velasco-Miguel et al, 1999). One of the predominant genes identified by the Kley laboratory was PA26 (p53-activated protein #26, also known as sestrin 1).…”

“…In vivo data, however, suggests that the predominant transcript/protein is the PA26-T2 variant. Moreover, the T2 variant is also upregulated by serum deprivation (Velasco-Miguel et al, 1999). This latter characteristic has been used to further classify PA26 as a Growth Arrest and DNA Damage (GADD) inducible gene.…”

Gene expression in Sinclair swine with malignant melanoma

“…CCAR1, downregulated 3-fold in inguinal lymph nodes with melanoma, mediates apoptosis induction, which involves sequestration of 14-3-3 protein(s) and altered expression of multiple cell cycle regulatory genes including MYC, CCNB1 and CDKN1A (Rishi et al, 2003). SESN1, a potential regulator of cellular growth (Velasco-Miguel et al, 1999), was downregulated by ,3-fold and 2-fold in melanoma liver and lungs, respectively. Gene expression values of samples obtained from the melanoma-afflicted pig were divided by those of the corresponding samples from the non-melanoma pig, to provide differential gene expression ratios.…”