Zhang CC, Steele AD, Lindquist S, Lodish HF.
Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal.
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2184-9.
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This is the first time that the prion protein has been shown to be implicated in hematopoietic stem cell survival or proliferation. Such a role for prion protein is unexpected since most prion protein mutations affect the nervous system and not the peripheral systems. However, it is unclear why the prion-null mice do not develop problems with the hematopoietic system with age, since a lack of replenishment in these mice would likely lead to eventual problems with age or when the mice are submitted to certain daily stresses that can happen even in controlled environments (like infections).
The fact that the passage in sequential transplantations decreases the number of cells while the null mice have no problems may indicate that the cells under the stress of isolation initiate mechanisms of cell death. We now have strong evidence for the role of prion protein against Bax-mediated cell death in human neurons and in the breast carcinoma MCF7 cell line (Bounhar et al., 2001; Roucou et al., 2003; Roucou et al., 2005), and PrP has also been shown to prevent TNFα-mediated cell death in MCF7 cells (Diarra-Mehrpour et al., 2004). Therefore, one possible explanation of the results is that the stem cells undergo Bax activation during the isolation and transplantation procedure and the presence of PrP prevents Bax-mediated cell death.
PrP has been shown to play a role in stimulated lymphocyte proliferation (Cashman et al., 1990; Mabbott et al., 1997), so the idea of PrP acting as a receptor for certain molecules is not entirely novel. Nevertheless, this is an interesting manuscript that brings forth the often ignored normal function of prion protein, a protein that is expressed in many tissues, often at fairly high levels.
Bounhar Y, Zhang Y, Goodyer CG, LeBlanc A.
Prion protein protects human neurons against Bax-mediated apoptosis.
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Diarra-Mehrpour M, Arrabal S, Jalil A, Pinson X, Gaudin C, Piétu G, Pitaval A, Ripoche H, Eloit M, Dormont D, Chouaib S.
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Mabbott NA, Brown KL, Manson J, Bruce ME.
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Roucou X, Guo Q, Zhang Y, Goodyer CG, Leblanc AC.
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Roucou X, Giannopoulos PN, Zhang Y, Jodoin J, Goodyer CG, LeBlanc A.
Cellular prion protein inhibits proapoptotic Bax conformational change in human neurons and in breast carcinoma MCF-7 cells.
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Zhang et al. show that the physiological form of the prion protein, PrPC, is expressed on hematopoietic stem cells, and may play a role in hematopoietic stem cell renewal. The authors speculate that PrPC might be a (co)receptor, protecting hematopoietic stem cells from apoptosis. This study represents one of many showing a putative function for PrPC. It differs from many other studies in that the relevance of this putative function is demonstrated in vivo.
A number of points come to mind:
There is no shortage of putative functions of PrPC. As a matter of fact, PrPC has been shown to bind copper (Brown et al., 1997); have antiapoptotic properties (Zanata et al., 2002); possess superoxide dismutase activity (Brown and Besinger, 1998); activate intracellular tyrosine kinases (Mouillet-Richard et al., 2000); and interact with Hsp60 (Watarai et al., 2003), among other things. If that seems confusing, it only gets worse if one looks at PrPC/PrPSc binding proteins. PrPC/PrPSc has been shown to bind to Bcl-2 (Kurschner et al., 1995), caveolin (Gorodinsky and Harris, 1995), the laminin receptor precursor (Rieger et al., 1997), plasminogen (Fischer et al., 2000), and N-CAM (Schmitt-Ulms et al., 2001).
Will the proposed, hematopoietic stem cell-related function of PrPC stand the test of time? The answer to date is uncertain. If the sole purpose of PrPC would relate to the hematopoietic system, then why is its expression orders of magnitude higher in the central nervous system?
Looking at all of these studies, and also taking into account that PrPC is extremely conserved throughout evolution and highly expressed in several tissue compartments including the central nervous system, the hematopoietic system, and the musculoskeletal system, one may consider that “the” PrPC function might not exist. Perhaps PrPC executes a multitude of functions. The challenge will be to find out how these different pieces of the puzzle fit together.
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Watarai M, Kim S, Erdenebaatar J, Makino S, Horiuchi M, Shirahata T, Sakaguchi S, Katamine S.
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Zanata SM, Lopes MH, Mercadante AF, Hajj GN, Chiarini LB, Nomizo R, Freitas AR, Cabral AL, Lee KS, Juliano MA, de Oliveira E, Jachieri SG, Burlingame A, Huang L, Linden R, Brentani RR, Martins VR.
Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection.
EMBO J. 2002 Jul 1;21(13):3307-16.
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