BAG1

Official Full Name

BAG cochaperone 1

Organism

Homo sapiens

GeneID

573

Background

The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein encoded by this gene binds to BCL2 and is referred to as BCL2-associated athanogene. It enhances the anti-apoptotic effects of BCL2 and represents a link between growth factor receptors and anti-apoptotic mechanisms. Multiple protein isoforms are encoded by this mRNA through the use of a non-AUG (CUG) initiation codon, and three alternative downstream AUG initiation codons. A related pseudogene has been defined on chromosome X. [provided by RefSeq, Feb 2010]

Synonyms

HAP; BAG-1; RAP46;

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Detailed Information

The BAG1 protein (Bcl-2–associated athanogene) was initially identified as a binding partner of the anti–cell death protein Bcl-2 and was shown to be involved in the regulation of apoptosis. However, subsequent studies revealed a plethora of additional partner proteins of BAG1, and a wide variety of cellular functions were assigned to BAG1, ranging from transciptional regulation to the control of cell migration.

BAG-1 is an Hsc70 nucleotide exchange factor

BAG1 exists as multiple isoforms in the mammalian cytosol, at least 4 isoforms can be distinguished: BAG1L, BAG1M, BAG1, and BAG1S. The amino terminal lengths of the isoforms are different. Despite this heterogeneity at the amino terminus, all isoforms share a central domain whose structure is associated with a conserved domain that degrades the ubiquitin and carboxy terminus of approximately 100 amino acids, termed BAG domain. The BAG domain is sufficient for Hsc70 binding and regulation the interaction of the co-chaper with the ATPase domain of Hsc70. Binding to the ATPase domain results in a strong acceleration of the homeostatic ATPase activity of the chaperone protein. This ATPase-stimulating activity of BAG1 is critically dependent on the additional presence of Hsp40. It was therefore concluded that BAG1 stimulates ADP release from Hsc70 after an initial Hsp40-induced conversion of the chaperone into the ADP-bound form, and experimental evidence for this notion was provided. The findings identify BAG1 as a nucleotide exchange factor of Hsc70. Over the past few years, many of these functions have been assigned to BAG1. For example, overexpression of BAG1 in cell culture experiments renders cells more resistant to apoptosis, particularly in cooperation with Bcl-2. The interaction with bcl-2's bag-1 is dependent on ATP, which may mean the participation of Hsc70. The stress-signaling kinase was described to be a direct binding partner of BAG1, association with BAG1 results in a stimulation of the kinase activity of Raf-1 and causes cell proliferation. Remarkably, the binding sites for Raf-1 and Hsc70 on BAG1 overlap, and the 2 proteins therefore bind to BAG1 in a mutually exclusive manner.

Fig. 1. The Basics of BAG1 Chaperoning. (Calderwood SK et al. Trends in biochemical sciences. 2016).

BAG1 worked as a nuclear regulator

Overexpression of BAG1 inhibits very broad drug-induced caspase activation and apoptosis in different cell types, for example chemotherapeutic agents, radiation and growth factor withdrawal. Therefore, in addition to contributing to reduced cell death in cancer development, BAG1 may also contribute to resistance to important therapeutic modalities. The finding that BAG1 can independently associate with Raf-1 or Bcl-2 provides at least two potential mechanisms by which BAG1 promotes survival. Heat shock proteins are also necessary for cell survival and direct activation of these functions is important. Suppression of apoptosis might contribute to the ability of BAG1 to promote metastatic spread. Alternatively, increased metastasis can be mediated through enhanced cell motility.

A second key function of BAG1 of likely importance for cancer is regulation of nuclear hormone receptors. BAG1 potentiates activity of oestrogen receptors (ER), which mediates proliferative, and estrogen-dependent response to hormone-dependent cancer is the goal of anti-hormone therapy such as tamoxifen. The androgen receptor (AR) is important in prostate cancer and BAG-1 increases sensitivity of AR expressing cells to androgens and decreases sensitivity to cyproterone acetate, an anti-androgen used clinically in the treatment of prostate cancer. Before the nuclear hormone receptors are activated, they interact with the molecular partners in the cytosol to attain a folding state capable of binding their corresponding ligands. The first steps of receptor maturation depend on the action of Hsc70, suggesting that BAG1 might interfere with these initial folding events by virtue of its substrate release activity.

In fact, the regulatory role of BAG1 on nuclear receptors depends on the presence of the BAG domain and thus most likely involves a modulation of Hsc70 function. The situation may change when BAG1 enters the nucleus. A cluster of lysine and arginine residues present at the amino terminus of BAG1M and BAG1L was recently shown to mediate a non-sequence specific binding of the co-chaperone to DNA. The DNA-binding domain enables BAG1M and apparently also BAG1L to activate transcription. Moreover, the DNA-binding domain must be present on the co-chaperone together with the Hsc70-interacting BAG domain to achieve an inhibition of glucocorticoid receptor–dependent transcription. The co-chaperone appears to use its DNA-binding domain to recruit Hsc70 to chromosomal loci and to modulate chaperone-assisted steps during transcription. These findings are particularly exciting with respect to a recent report implicating chaperones in transcription regulation. In this report molecular chaperones were shown to promote the disassembly of transcriptional regulatory complexes, thus enabling regulatory machineries to detect and respond to signaling changes.

References:

Alberti S, Esser C, Höhfeld J. BAG-1—a nucleotide exchange factor of Hsc70 with multiple cellular functions. Cell Stress & Chaperones. 2003;8(3):225-231.
Calderwood SK, Gong J. Heat Shock Proteins Promote Cancer: It’s a Protection Racket. Trends in biochemical sciences. 2016;41(4):311-323.
Cutress RI, Townsend PA, Brimmell M, Bateman AC, Hague A, Packham G. BAG-1 expression and function in human cancer. British Journal of Cancer. 2002;87(8):834-839.
Rampelt H., Mayer M.P., Bukau B. (2018) Nucleotide Exchange Factors for Hsp70 Chaperones. In: Calderwood S., Prince T. (eds) Chaperones. Methods in Molecular Biology, vol 1709. Humana Press, New York, NY.
Shen Z1, Li Y2, Zhao C3, Wang F1, Zhou R1, Chen G1. miR‑494‑BAG‑1 axis is involved in cinobufacini‑induced cell proliferation and apoptosis in gastric cancer. Mol Med Rep. 2018 May;17(5):7435-7441.

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