Overexpression of the Oncoprotein Prothymosin α Triggers a p53 Response that Involves p53 Acetylation

Abstract

Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and B-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin A (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation. (Cancer Res 2006; 66(6): 3137-44)

Immunocytological and Preliminary Immunohistochemical Studies of Prothymosin α, a Human Cancer–associated Polypeptide, With a Well-characterized Polyclonal Antibody

“…Increased intracellular expression of ProTa, which has been thought to be an oncoprotein (Karapetian et al 2005;Kobayashi et al 2006), has been observed in several types of human cancer. Recently, several groups have applied IHC techniques and reported that ProTa is overexpressed in various cancers, e.g., gastric (Leys et al 2007), prostate (Suzuki et al 2006), and thyroid (Letsas et al 2005) cancer, and might therefore be considered as an intracellular tumor biomarker.…”

Abiotic Stress-Induced Programmed Cell Death in Plants: A Phytaspase Connection

“…ProTa is a proliferation-related protein localizing in the nucleus where it is engaged in activity regulation of several stress-related transcription factors, such as p53 tumour suppressor and Nrf2 (Karapetian et al, 2005;Kobayashi et al, 2006;Zakharova et al, 2008). Caspase-3-mediated cleavage detaches a short C-terminal peptide of ProTa.…”

Transgenic expression of prothymosin alpha on zebrafish epidermal cells promotes proliferation and attenuates UVB-induced apoptosis

“…It has been demonstrated that overexpression of Ptmaa causes apoptosis in cultured cells (Kobayashi et al 2006). However, Ptma may function as an apoptosis inhibitor in some physiological conditions, such as under stress, stroke or ischemia (Letsas and Frangou-Lazaridis 2006;Fujita et al 2009).…”

“…Knockdown of Ptma synthesis by antisense oligonucleotides and RNAi leads to cell division arrest and inhibits prostate tumor cell growth and invasion in vitro (Sburlati et al 1991;Suzuki et al 2006). Ptma also plays a role in the mitochondria or p53 pathways to regulate apoptosis (Markova et al 2003;Kobayashi et al 2006). In addition, Ptma could be used as a potential tumor marker for early detection, estimation of tumor aggressiveness, and treatment response in certain types of human cancers, such as breast (Magdalena et al 2000), lung (Sasaki et al 2001a), prostate (Suzuki et al 2006), bladder (Tzai et al 2006), gastric (Leys et al 2007) and rectal cancer (Ojima et al 2007).…”