HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma

Abstract

Apoptosis is a fundamental biological process used to eliminate unwanted cells in a multicellular organism. An increasing number of regulatory proteins have been identified that either promote or inhibit apoptosis. For tumors to arise, apoptosis must be blocked in the transformed cells, for example by mutational overexpression of anti-apoptotic proteins, which represent attractive target proteins for molecular therapy strategies. In a functional yeast survival screen designed to select new anti-apoptotic mammalian genes, we have identified the chromosomal high-mobility group box-1 protein (HMGB1) as an inhibitor of yeast cell death induced by the pro-apoptotic Bcl-2 family member Bak. The C-terminal 33 amino acids of HMGB1 are dispensable for this inhibitory function. HMGB1 is also able to protect mammalian cells against different death stimuli including ultraviolet radiation, CD95-, TRAIL-, Casp-8-, and Bax-induced apoptosis. We found high HMGB1 protein levels in human primary breast carcinoma. Hmgb1 RNA levels are changing during different stages of mouse mammary gland development and are particularly low during lactation and involution. These data suggest that HMGB1 may participate in the regulation of mammary gland apoptosis and that its high expression level promotes tumor growth because of its anti-apoptotic properties.

The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential

“…We performed a functional yeast survival screen with a human breast carcinoma-derived cDNA library in order to identify novel anti-apoptotic proteins involved in tumorigenesis. 17,18 Among others, we isolated a cDNA clone coding for an N-terminal deletion mutant of the anti-apoptotic Aven protein. This clone, which efficiently suppressed yeast cell death induced by the proapoptotic C. elegans protein CED-4 (see Supplementary Figure 1), lacks the coding sequence for the N-terminal 179 aa (amino acid) of the protein (DN-Aven 180-362).…”

HMGB1 was a pivotal synergistic effecor for CpG oligonucleotide to enhance the progression of human lung cancer cells

“…[8][9][10] Recently, accumulating data suggested that HMGB1 expression was correlated with tumor development. [10][11][12][13] Upregulated expression of HMGB1 has been found in many tumor types including lung cancer. 3 However, high-mobility group box 1 (hMGB1) has been implicated in a variety of biologically important processes, including transcription, DNa repair, differentiation, development and extracellular signaling.…”

Expression of Bax in yeast affects not only the mitochondria but also vacuolar integrity and intracellular protein traffic

“…Conversely, Bax-expression in plants causes localized tissue collapse in a manner resembling the hypersensitive response, a PCD response of plants in defense against pathogens [5]. Moreover, human or plant genes isolated from yeast genetic screens for Bax or Bak suppression have been associated with pro-survival effects when expressed in their native or a heterologous context [6][7][8][9].…”