BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

Two BAG3 forms have been described so far: one is the full-lenght product of the bag3 gene having an apparent mass of 74 kDa, the other one is a shorter BAG3 protein found in association to neuronal synaptosomes 2, [9] [10] [11] (Figure 1b) . The BAG3 full-length protein is localized in the cytoplasm, mainly concentrated in the rough endoplasmic reticulum; on cell exposure to stressors, a slightly different molecular weight variant of this form can also be observed, and both co-exist in some cell types and run as a doublet in a standard western blot. The origin of this doublet is currently unknown, but it could derive from post-translational modifications as phosphorylations, indeed BAG3 protein contains several serinerich motifs and 10 tyrosine residues. Tyrosine phosphorylation of BAG3 occurs on EGF stimulation in human breast cancer cell lines. 12 This post-translational variant of BAG3 protein appears also to be associated to Bruton's tyrosine kinase (Btk) protein in Defew cells on oxidative stress induction. 13 Recently, a shorter form of BAG3 (40 kDa) has been characterized by immunoprecipitation from neural synaptosomes homogenates and successive mass spectrometry, 11 again it is yet unknown whether this form derives from the alternative splicing or proteolytic processing. BAG3 expression has also been observed in the nuclei of some cell types, including pancreatic carcinoma cells (unpublished results from our laboratory). Interestingly, BAG3 was shown to localize in nuclei of cells infected by some viruses; those findings suggest an involvement of BAG3 in viral expression and/or replication, and indeed some reports indicate a requirement for BAG3 for virus gene expression and/or viral progeny production. 12, [14] [15] [16] [17] [18] In keeping with those results, viral infection was shown to induce the expression of BAG3, as a possible tool contributing to virus life cycle. 12, 19 In humans, bag3 gene expression is constitutive in myocytes, a few other normal cell types and several primary tumors or tumor cell lines (lymphoid or myeloid leukemias, lymphomas, myeloma, neuroblastoma, pancreas, thyroid, breast and prostate carcinomas, melanoma, osteosarcoma, kidney, colon and ovary cancers, glioblastoma). [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] It is instead induced in different normal cell types (leukocytes, epithelial and glial cells, retinal cells) by a variety of stressors, such as oxidants, high temperature, serum deprivation, heavy metals, HIV-1 infection, ELF exposure, electrophile stress, hemodialysis treatment, pulsed ultrasound, retinal light damage, kanaic acid-induced seizure and transient forebrain ischemia. 2, 10, 14, 19, 35, [37] [38] [39] [40] [41] [42] [43] [44] The expression of stress-responsive genes is regulated by the heat shock transcription factors (HSFs), 45 including HSF1, that is required for tumor initiation and maintenance in a variety of cancer models. 46 bag3 gene promoter activity is regulated by HSF1, 31, 47, 48 again suggesting a role in tumor formation. Other known transcription factors that are known to regulate bag3 expression are Egr1 29 AibZIP 26 and WT1. 49 The regulation by WT1 is of particular interest because of the role played by this transcription factor in human leukemias 50 (see the section BAG3 in leukemias). Furthermore, in some cell types bag3 expression seems to be controlled by its own product. 51 A number of drugs -proteasome inhi