Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Pin1 and Apoptosis in AD
 | As Czech et al. (2000) have recently stated in their review article: ".....several lines of evidence support a role of apoptosis in the massive neuronal loss observed (inAD) ."E.g., see Anderson et al. (2000) and other references. |
| Yuan and Yankner (2000)
report in
Nature that neuronal apoptosis has a potentially important role
in neurodegenerative diseases (as well as an involvement in the 'sculpturing'
of the developing brain). They suggest that the precise elucidation of
such neuronal cell death might provide additional points for therapeutic
interventions. |
| While there is no doubt that death is
the ultimate fate
of at least a significant proportion of AD-affected
neurons, there is still much debate about the nature of this death. There
are those (del Rio and Velez-Pardo, 2001) who dispute that the
involvement of apoptosis in AD has been truly confirmed, as the more terminal
phases, such as chromatin condensation, apoptotic bodies, and blebbing,
are rarely (except e.g. Su et al., 1994) seen in AD. However, most
researchers appear to agree that some sort of apoptosis occurs, albeit,
perhaps, in a different form from that occurring in normal tissues. |
| Although there is apparent consensus
that some form of apoptosis takes place, the latter is but
one of an increasing number of programmed cell death (PCD) mechanisms that
can occur in cells and that may be triggered concurrently. These latter
have recently been reviewed (Leist and Jäättelä, 2001)
) with the conclusion that, specifically in regard to neurons, there appear
to be extra controls for caspase activation and that caspase-independent
death pathways may be preferentially-activated. |
| The stimulation of mitotic
events
in AD-affected neurons
may well contribute to this apoptosis
(e.g. see Mattson, 2000; Offen et al., 2000; Yuan and Yankner,
2000). |
| Pin1 may have a key role in this apoptosis for the following reasons . Firstly, deletion of Pin1 activity in HeLa cells causes mitotic arrest and apoptosis (Lu et al. 1996). Secondly, 'spurious' mitotic events in affected neurons would create numerous nuclear targets which, if not bound by Pin1 (due to depletion of nuclear Pin1 because of its redirection to the cytoplasmic tangles) would be likely to contribute to nuclear instability and thence apoptosis (e.g. Cdc25: see diagram below). |
 | A possible direct mechanism whereby Pin1 depletion might invoke apoptosis is offered up by the recent suggestion (Pathan et al., 2001 ) that Bcl-2, a potent inhibitor of apoptosis (Kroemer, 1997 ; Shimizu et al., 1996) might be a Pin1 target protein. Bcl-2 has been shown to be located on cytosol-facing membranes of the nucleus, endoplasmic reticulum (ER) and the mitochondria (in transgenic mouse cell lines; Lithgow et al., 1994), although others have suggested that the mitochondrial localisation is more predominantly at the inner membrane and cristae (in rat liver; Motoyama et al., 1998). Pathan et al. (2001 ) showed that phosphorylation of Bcl-2 is induced at serine residues when microtubule-targetted drugs are used to arrest tumour cells. |
| Phosphorylation of Bcl-2 inactivates its anti-apoptotic role (Yamamoto et al., 1999) and promotes its increased association with Pin1 (Pathan et al., 2001). Phosphorylation of a proline-rich loop region (probably by Cdc2) creates potential Pin1-binding motifs, and Pathan et al. suggested that Pin1 binding might block the conformational changes required for Bcl-2’s normal, cytoprotective, ion-channel forming activities (Schendel et al., 1997). There is evidence that Bcl-2 is phosphorylated transiently during mitosis (Yamamoto et al., 1999 ), thereby presumably creating an ‘apoptotic opportunity’ should aberrant chromosomal segregation or cytokinesis occur. |
| During neurodegeneration, increased (neuronal ‘cdc2-like’) Cdk5 activity and elevated cytoplasmic levels of Pin1 would create a cellular situation akin to mitosis with regard to potential prolonged admixing of phosphorylated Bcl-2 and Pin1 protein. In this way, redirection of Pin1 to the cytoplasm in itself - apart from the effects of concomitant nuclear depletion (Lu et al., 1999; Thorpe et al., 2001) - might also contribute to apoptosis (see diagram below). |
| In regard to the latter, treatment of neuronal cell cultures with beta-amyloid peptide has been shown to promote the up-regulation (of both mRNA and protein levels) of Bcl-xL, a member of the Bcl-2 family (Luetjens et al., 2001). If upregulation and concomitant phosphorylation of Bcl-2 occurs similarly in AD neurons then binding of Pin1 to phosphorylated Bcl-2 could initiate a cascade of events leading ultimately to apoptosis. |
| Very recently, it has been reported that Inhibition of Pin1 induces caspase-3-mediated apoptosis of human peripheral blood eosinophils (Shen et al., 2005) |
(1) Lu_PJ, Wulf_G, Zhou_XZ, Davies_P, Lu_KP (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. NATURE 399: 784-788
(2) Zhou, XZ, Kops, O, Werner, A, Lu, PJ, Shen, MH, Stoller, G, Kullertz, G, Stark, M, Fischer, G and Lu, KP (2000) Pin1 -dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau protein. MOLECULAR CELL 6: 873-883
(3) Crenshaw DG, Yang J, Means AR, Kornbluth S (1998) The mitotic peptidyl-prolyl isomerase, Pin1 , interacts with Cdc25 and Plx1 . EMBO J 17:1315-1327
(4) Harris, PLR, Zhu, XW, Pamies, C, Rottkamp, CA, Ghanbari, HA, McShea, A, Feng, Y, Ferris, DK and Smith, MA (2000) Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes. NEUROBIOLOGY OF AGING 21: 837-841
(5) Feng Y, Hodge DR, Palmieri G, Chase DL, Longo DL, Ferris DK (1999) Association of polo-like kinase with alpha-, beta- and gamma-tubulins in a stable complex. Biochemical Journal 339: 435-442
(6) Vogelsberg-Ragaglia, V, Schuck, T, Trojanowski, JQ and Lee, V. M.-Y. (2001) PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus. Experimental Neurology 168: 402-412
(7) Thorpe, J.R., Morley, S.J. and Rulten, S.L . (2001) Utilising the Peptidyl-Prolyl Cis-Trans Isomerase Pin1 as a Probe of its Phosphorylated Target Proteins: Examples of Binding to Nuclear Proteins in a Human Kidney Cell Line and to Tau in Alzheimer’s Diseased Brain. J. Histochem. Cytochem. 49: 97-108
(8) Ding, XL, Husseman, J, Tomashevski, A, Nochlin, D, Jin, LW and Vincent, I (2000) The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer's disease. American Journal Of Pathology 157: 1983-1990
(9) Pathan, N, Aime-Sempe, C, Kitada, S, Haldar, S and Reed, JC (2001) Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1. Neoplasia 3: 70-79
(10) Kumagai, A and Dunphy, WG (1999) Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25. Genes Dev 13: 1067-1072
References
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Czech C, Tremp G and Pradier L (2000) Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms. Prog Neurobiol 60: 363-84
del Rio, MJ and Velez-Pardo, C (2001) Apoptosis in neurodegenerative diseases: Facts and controversies. REVISTA DE NEUROLOGIA 32: 851-860
Kroemer, G (1997) The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nature Medicine 3: 614-620
Leist M and Jäättelä, M (2001) Four Deaths And A Funeral: From Caspases To Alternative Mechanisms. Nature Reviews Molecular Cell Biology 2, 589 -598
Lithgow, T, Vandriel, R, Bertram, Jf and Strasser, A (1994) The protein product of the oncogene bcl-2 is a component of the nuclear-envelope, the endoplasmic reticulum, and the outer mitochondrial-membrane. Cell Growth & Differentiation 5: 411-417
Lu KP, Hanes SD and Hunter T (1996) A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380: 544-547
Lu PJ, Wulf G, Zhou XZ., Davies P and Lu KP (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399: 784-788
Luetjens, CM, Lankiewicz, S, Bui, NT, Krohn, AJ, Poppe, M and Prehn, JHM (2001) Up-regulation of Bcl-xL in response to subtoxic beta-amyloid: Role in neuronal resistance against apoptotic and oxidative injury. NEUROSCIENCE 102: 139-150
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Pathan, N, Aime-Sempe, C, Kitada, S, Haldar, S and Reed, JC (2001) Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1. Neoplasia 3: 70-79
Schendel SL, Xie ZH, Montal MO, Matsuyama S, Montal M, Reed JC (1997) Channel formation by antiapoptotic protein Bcl-2. Proceedings of The National Academy of Sciences of the United States Of America 94: 5113-5118
Shen ZJ, Esnault SJ, Malter JS (2005) Inhibition of the peptidyl-prollyl isomerase (PPlase) Pin1 induces caspase-3-mediated apoptosis of human peripheral blood eosinophils. Clinical Immunology 115: S50-S51
Shimizu S, Eguchi Y, Kamiike W, Itoh Y, Hasegawa J, Yamabe K, Otsuki Y, Matsuda H, Tsujimoto Y (1996) Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-X(L). Cancer Research 56: 2161-2166
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Thorpe, J.R., Morley, S.J. and Rulten, S.L. (2001) Utilising the Peptidyl-Prolyl Cis-Trans Isomerase Pin1 as a Probe of its Phosphorylated Target Proteins: Examples of Binding to Nuclear Proteins in a Human Kidney Cell Line and to Tau in Alzheimer’s Diseased Brain. J. Histochem. Cytochem. 49: 97-108
Yamamoto K, Ichijo H And Korsmeyer SJ (1999) Bcl-2 is phosphorylated and inactivated by an ask1/jun n-terminal protein kinase pathway normally activated at G(2)/M. Molecular and Cellular Biology 19: 8469-8478
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