Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Pin1 and Cell Cycle Events in AD
 | In HeLa cells, Pin1 depletion causes mitotic arrest
and apoptosis, whilst overexpression results in G2 phase arrest
(Lu et al., 1996). |
| Additionally, very recent work has revealed that
Pin1 is overexpressed in breast cancer (Wulf et al., 2001
); it was suggested that this overexpression promotes oncogenesis through
the interaction of Pin1 with c-Jun, thereby increasing the latter’s transcriptional
activity, resulting in increased cellular levels of cyclin D1. |
| There is much recent research interest in increased
expression of cell cycle-related proteins in AD
(e.g. see
Husseman et al., 2000; Vincent et al., 1996 and many
other references). |
| Although neurons of the adult brain are normally
considered to be in a ‘terminally-differentiated’ state
,
accumulation of mitotic phosphoepitopes - via the spurious re-expression
and activation of Cdc2/cyclin B (the mitotic phase regulating kinase)
and associated cell cycle-related proteins - has been shown in AD and
has attracted much research interest (Arendt et al., 1998 & 2000
; Busser et al., 1998 ; Cataldo et al., 2000; Ding et
al., 2000 ; Dranovsky et al., 2001; Giovanni et al.,
1999 ; Harris et al., 2000; Husseman et al., 2000;
Husseman et al., 2001; Illenberger et al., 1998; Nagy et al., 2000
; Vincent et al., 1996). It has been described as an ‘interrupted’
mitotic process which leads to associated cytoskeletal abnormalities (including
tangle
formation) and, ultimately, apoptosis (Anderson et al., 2000
; Engidawork et al., 2001; Mattson, 2000). |
| The cellular signal transduction pathways
initiating these cell-cycle events
are triggered by the various
deleterious effects of AD upon the neurons, which might, for example, include
beta-amyloid
protein-induced microglia (Wu et al., 2000). |
| Specific examples of the cell-cycle proteins
elevated in AD
which are also known Pin1 targets include Cdc25A
(Ding et al., 2000) and polo-like kinase (Plk1; Harris et al.,
2000 ). The Cdc25 phosphatases play a key role in cell-cycle progression
by activating the cyclin-dependent kinases, including cdc2/cyclin B. Plk1
(Lane and Nigg, 1997) is a regulator of Cdc25. Cdc25A is associated
with both neuritic plaques
and tangles
and its tyrosine dephosphorylating activity is elevated (Ding
et al., 2000). Also, as this phosphatase is activated by phosphorylation
by cdc2/cyclin B, the Cdc25A exhibited increased mitotic phosphoepitope-specific
antibody (MPM-2)-reactivity, and colocalized with the MPM-2 immunoreactivity
in AD neurons. These data suggest that Cdc25A participates in mitotic activation
during neurodegeneration. |
| Pin1 protein may modulate Cdc2/cyclin B
, and thus cell cycle control, through its interactions with Cdc25
and Plk1 (Crenshaw et al., 1998). Although the mitotic activation
of Cdc25 is not fully understood, certain conclusions have been drawn by
Stukenberg and Kirschner (2001) from their most recent
work, including the effect of (>95%) Pin1 (immuno-)depletion. This study
demonstrated that Pin1 could produce conformational changes in Cdc25 (as
previously reported; Zhou et al., 2000), but, additionally, they
showed that it was acting catalytically. Pin1 could either activate or
inhibit Cdc25 phosphatase activity, dependent upon its phosphorylation status:
if phosphorylated by Cdc2 alone (as in lag phase), Cdc25 is inhibited by
Pin1, but, if phosphorylated by both Cdc2 and Plx (as in G2/M transition),
Pin1 increases the phosphatase activity of the protein. It was this
latter activation that was suggested to be mediated by a conformational
change in the Cdc25 protein, with the experimental data indicating a cis-trans
isomerization of proline residues in the folded Cdc25 protein. Depletion
of Pin1 halted the full activation of Cdc25, with a resultant slower, less-concerted
action of Cdc2. If this scenario occurred within similarly nuclear Pin1-depleted
AD-affected neurons, then an ensuing aberrant, interrupted mitosis might
follow, giving rise to nuclear instability and ultimately to cell death
(see Pin1 and Apoptosis). |
| Other Pin1 targets
such as RNA polymerase
II (Bregman et al., 2000; Husseman et al., 2001), rab4 ( Cataldo
et al., 2000) and c-Jun (Shoji et al., 2000) have been similarly
shown to be upregulated in AD and, quite probably, future research will
reveal further examples. Overall, increased expressions of such proteins
would create more potential Pin1 binding motifs and an additional reason
why insufficient levels of available, soluble Pin1 protein in the neurons
(especially in the nucleus) could have a potentially damaging effect on
their ultimate fate. |
|
In regard to RNA polymerase II (RNAP II), Husseman
et al. (2001) have just published data on cdc2 phosphorylation
of RNAP II in AD brain. In mitosis, cdc2 phosphorylates and inhibits
(the transcriptional regulator) RNAP II. In AD brain, RNAP II was found
to be highly phosphorylated and to relocate to the cytoplasm in association
with cdc2. These mitotic-like events correlated with decreased poly-A RNA
in affected neurons and preceded tau phosphorylation and tangle formation.
Overall, they suggested that activation of cdc2 contributes to neuronal
degeneration by inhibiting RNAP II and thence those cellular processes dependent
on transcription. |
| Recently, data from a Drosophila tauopathy
model suggests that tau phosphorylation is upstream of cell cycle activation
(Khurana et al., 2006).
This would lend
more support to our hypothesis that shorfalls of endogenous Pin1 would be
deleterious to neuronal function, rather than the opposing view that Pin1
might instigate neurodegeneration via cyclin D1 (and thence cell cycle)
activation.
|
| Also see 'Possible Pin1 Binding Events in AD' diagram. |