Abstract
Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110–124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression.
Highlights
BAG3 was originally identified by yeast two-hybrid screening using the ATPase domain of the heat shock protein (Hsp) (heat shock cognate (Hsc)/Hsp) 70 as a bait.[1]
From the first evidence of BAG3-mediated survival in B-cell chronic lymphocytic leukemia (B-CLL),[21] a number of reports confirmed the anti-apoptotic activity of the protein in tumors of the hematopoietic[2,13,21,22,25,28,30,39,40,49] and other[2,20,24,25,29,31,34,36,37,44] compartments
Two principal elements contribute to the role of BAG3 in vast range of tumors: bag[3] induction by HSF1,47 a transcription factor activated in many cancer types;[46] and BAG3 ability to sustain of NF-kB activity.[76]
Summary
BAG3 expression has been observed in the nuclei of some cell types, including pancreatic carcinoma cells (unpublished results from our laboratory). Mice with homozygous disruption of bag[3] gene develop post birth an early fulminant myopathy[23] and, in humans, a heterozygous p.Pro209Leu mutation in BAG3 protein was recently recognized to be responsible for a severe muscular dystrophy with cardiomyopathy and severe respiratory insufficiency.[57,58,59] In one of the three studied families carrying this mutation, an axonal neuropathy was present This observation is intriguing in view of the reported localization of a 40 kD form of BAG3 in synaptosomes[11] and of the above discussed role of BAG3 in CNS. It is likely that the availability of the different partners underlies the different mechanisms through which BAG3 exerts its anti-apoptotic activity in different cell types
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