HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma.
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.
Brezniceanu
Marie-Luise
ML
Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany.
Völp
Kirsten
K
Bösser
Susanne
S
Solbach
Christine
C
Lichter
Peter
P
Joos
Stefan
S
Zörnig
Martin
M
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D002460:Cell Line; D019610:Cytoprotection; D005260:Female; D018507:Gene Expression Regulation, Developmental; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012568:Schizosaccharomyces / Q000166:cytology / Q000235:genetics; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein
C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; C494774:Bak1 protein, rat; D024243:HMGB1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein