cAMP promotes degradation of Cyclin D3 via GSK-3b
Kofi
This new finding establishes an interesting link between GSK-3b
(overactivated by insulin resistance), beta-catenin, nitric oxide, cGMP
and the androgen receptor (regulated by cyclin D3). It provides
tantalizing hints that ties insulin resistance together with increased
androgen signaling (acne, polycycstic ovarian syndrome, baldness, BPH,
etc.).
I wasn't a big believer in GSK-3b inhibition at first, but I'm getting
there. I thank those posters who brought it to my attention.
J Cell Sci. 2004 Sep 1;117(Pt 17):3769-3783. Epub 2004 Jul 13. Related
Articles, Links
Click here to read
cAMP-induced degradation of cyclin D3 through association with
GSK-3{beta}
Naderi S, Gutzkow KB, Lahne HU, Lefdal S, Ryves WJ, Harwood AJ,
Blomhoff HK.
Department of Medical Biochemistry, University of Oslo, P.O. Box
1112 Blindern, Oslo, N-0317, Norway.
In this study we report a new mechanism whereby cyclic AMP (cAMP)
regulates the cell-cycle machinery. We demonstrate that elevation of
intracellular levels of cAMP promotes degradation of cyclin D3 in
proteasomes, and that this occurs via glycogen synthase kinase-3beta
(GSK-3beta)-mediated phosphorylation of cyclin D3 at Thr-283. Elevation
of cAMP did not change the subcellular distribution of either cyclin D3
or GSK-3beta. However, cAMP promoted the interaction between cyclin D3
and GSK-3beta both in vitro and in vivo, indicating that
GSK-3beta-mediated phosphorylation of cyclin D3 might require the
association between the two proteins. These results demonstrate how cAMP
enhances degradation of cyclin D3. Furthermore, we provide evidence for
a novel mechanism by which GSK-3beta might phosphorylate unprimed
substrates in vivo.
PMID: 15252116 [PubMed - as supplied by publisher]
I present some interesting connections for you to consider. Sorry I
don't have the time to better organize my notes.
cyclins can be part of resistance to antiandrogen therapy in prostate
cancer (selenium and 17B estradiol also inhibit cyclins; selenium does
so by inducing cyclin-dependent kinase inhibitor p21(Waf1/Cip1) [PMID
11980647]; downregulation of p21Waf1 seems to result in a proliferation
of androgen receptors [PMID 11606392])) (Cyclin E might be responsible
for resistance of androgen deprivation in prostate cancer cells whereas
inducing Cyclin D might help; when telomeres shorten enough on
chromosomes, p21 triggers cell senescence); p21-activated kinase (PAK)
is responsible for freeing up Rac from RhoGDI for cell motility
<http://www.sciencedaily.com/releases/2004/07/040702092450.htm>;
Selective Estrogen Receptor Modulators like raloxifen/Evista and
taxol/tamoxifen (patented for hair growth) upregulate BMP-2 [PMID
12072396]); caffeine inhibits phosphorylation of Akt and GSK-3b in
cancer progression [PMID 15126379]
cyclic adenosine monophosphate (cAMP) turns on growth factors in nerve
cells; rolipram (which inhibits breakdown of cAMP) together with Schwann
cell transplants restore a good deal of function in injured spinal
cords; cAMP is low after spinal cord injuries
<http://www.sciencedaily.com/releases/2004/05/040524060214.htm>
deficiencies in genes for cAMP responsive element binding protein (CREB)
- a transcription factor - inclines lab mice to alcoholism; CREB
regulates brain function during development and learning and controls
early steps in turning on the expression of a new protein; CREB
regulates production of neuropeptide Y; low levels of NPY or CREB
correspond to anxiety and excessive alcohol consumption; alcohol
enhanced production of CREB and NPY in deficient mice
<http://www.sciencedaily.com/releases/2004/05/040526063645.htm>; GSK-3b
reduced cAMP-induced CCK (cholecystokinin) promoter activity and CREB
binding [PMID 15073527]; protein synthesis inhibitors stop production of
proteins in the brain and causes animals to lose long-term memory;
animals with CREB defects have trouble with long-term memory; likewise
CREB binding protein (CBP) is necessary for long-term memory, CPB is a
coactivator of transcription, acting with CREB to control genetic
expression; CPB atttaches acetyl groups to proteins and acetylates
histones; animals with defective CBP can regain long-term memory defects
with histone deacetylase inhibitors like Trichostatin A, a leukemia drug
<http://www.sciencedaily.com/releases/2004/06/040624093252.htm>;
calcineurin inhibition grows hair (probably because GSK-3 kinases
stimulate calcineurin signaling and GSK-3beta inhibits beta-catenin
[PMID 14701880]); endogenous calcineurin inhibits long term memory [PMID
11257222]
viagra (cGMP is produced as a result of NO release; viagra increases the
levels cGMP by preventing its breakdown) and another substance which
increases cAMP and L-arginine all block TGF-B1 created plaques by
inhibiting collagen I synthesis [PMID 14996430]; arginine, TGF-B
inhibitors and NO-releasers/mimetics (minoxidil) are all patented for
hair growth
niacin interferes with the cAMP/PKA pathway and massively stimulates
PGD2 formation (perhaps accounting for its benefit in atherosclerosis);
the major metabolite of PGD2, 15d-PGJ2), is the body's most potent
PPAR-gamma activator [PMID 15037193]; high doses of niacin thin the hair
glycogen synthase kinase-3beta is linked to insulin resistance and
diabetes and it blocks glycogen synthase activity; insulin stimulation
via PI3K causes Akt phosphorylation of GSK-3b which blocks GSK-3b from
being active; GSK-3b is inhibited by zinc ions, which increases glycogen
synthase activity, intracellular levels of beta-catenin and glucose
uptake in fat cells making zinc an insulin mimetic [PMID 12083774]
BMP-2 increases protein levels of beta-catenin, an N-cadherin-associated
Wnt signal transducer, and decreases levels of GSK-3B; BMP-2 induces
chondrogenesis via Wnt-3a; BMP-2 triggers upregulation of crosstalk
between beta-catenin and Smad-4; Wnt-3a decreases N-cadherin and GSK-3b
levels [PMID 12077113]; PGE2 modulates bone metabolism; human
mesenchymal stem cells express both COX-1 and COX-2; PGE2 levels are
higher than in osteoblastic cells due to higher expression of
membrane-associated PGE synthase (mPGES) regulated by early growth
response factor (Egr-1); treating these stem cells with a specific COX-2
inhibitor suppresses expression of BMP-2 (an effect blocked by an EP4
receptor agonist) therefore PGE2 increases BMP-2 expression via binding
to the EP4 receptor (minoxidil stimulates prostaglandin-H synthase
(PGHS)-1; anagen hair expresses prostaglandin receptor EP3 and EP4)
[PMID 15254968]
sustained nitric oxide inhibition in neurons induces apoptosis;
compounds which slowly release NO reverse this effect, as do cGMP and
caspase-3 inhibitors; NO deprivation decreases Akt and extra Akt
signaling enhances survival, indicating that endogenous NO counteracts
apoptosis via Akt/GSK-3b signaling (e.g., promotion of
beta-catenin/inhibition of GSK-3b) [PMID 12064469]; growth hormone may
also be antiapoptotic through this NO/Akt/GSK-3b pathway [PMID
15067206], just like eNOS [PMID 14687855, 12835404]; GSK-3b inhibitors
are antidepressants [PMID 15050857] and increase the survival of neurons
subjected to oxidative stress [PMID 15044068] and increase angiogenesis
[PMID 12167628]; GSK-3b enhances TNF-a activation of iNOS and NFKB
signals [PMID 12065308]; TNF-a plus high glucose activates GSK-3b long
term exposure to TNF-a promotes insulin resistance (compare with my
previous post on TNF-a and allergies)
the cox inhibitor celecoxib (Celebrex) happens to inhibit Akt signaling
in addition to Cox-2 which would be bad for nerves, hair, gut repair,
beta-catenin, etc. although this might make it a novel chemotherapy
agent <http://www.sciencedaily.com/releases/2004/07/040708003721.htm>,
celecoxib also inhibits IKappaBalpha kinase in cancer cells which blocks
NFKB activation via IKappaBalpha degradation [PMID 15265936]; for
celecoxib's effects on GSK-3b, see [PMID 15238462]
both NGF and IGF-I synergistically promote neurite growth in adult
sensory neurons via PI3K/Akt/GSK-3 pathway; inhibition of GSK-3 and MAPK
resulted in greater growth [PMID 12911620, 15207235]; NGF signaling via
PI3K/GSK-3b pathway activates APC
<http://www.unc.edu/news/newsserv/archives/jun04/pathway063004.html>;
inhibition of GSK-3b suppresses NF-kappaB in cancer tissue [PMID
14991743]; proteasome inhibition stimulates neurite outgrowth in
neuronal-like cell lines [PMID 10206996] but arrests NGF-stimulated
neurite outgrowth in sympathetic and sensory nerve cultures [PMID
14648596] however proteasome inhibition also prevents axonal
degeneration in NGF-deprived sympathetic neurons [PMID 128733380]; in
hypothalamic neurons, DHEA blocks Akt activity and prevents
phosphorylation of proapoptotic kinase GSK-3b (which keeps it in an
inactive state); IGF-I signaling protects these neurons from this
DHEA-induced apoptosis [PMID 15062551]; IGF-I is a hair growth factor
(and can be induced with agents like sophora, zinc, etc.); NGF is
patented for hair growth;
histamines activate TCF/beta-catenin transcription via GSK-3b
inhibition; this provides a link between inflammation and cancer
development; on the other hand, GSK-3b overactivation contributes to
insulin resistance, neurodegeneration, hair loss, etc. [PMID 14563838]
pretreatment with GSK-3 inhibitors protects neurons from NMDA
excitotoxicity [PMID 12960765] (since GSK-3b is elevated in insulin
resistance, this may explain the role insulin resistance plays in
neurodegeneration)
GSK-3b inhibitors block EGF-induced keratinocyte migration in scratch
wounds [PMID 12890758]; EGF is overactive both in baldness, acne and
prostate cancer
in oxidative stress injury of nerve cells, pretreatment with EGCG
downregulates PARP, caspase-3 cleavage, cytochrome C release, Akt and
GSK-3 while upregulating PI3K, phosphorylated Akt and phosphorylated
GSK-3 (i.e., EGCG activates PI3K/Akt and inhibits GSK-3 signaling) [PMID
14559356]; EGCG activates eNOS [PMID 14645258]; TNF-a plus insulin has
an additive effect on the phosphorylation of protein kinase B-alpha and
GSK-3b; short term exposure to TNF-a enhances insulin's effects whereas
long term exposure promotes insulin resistance [PMID 15026145]; EGCG
inhibits TNF-a and EGF;
in diabetic, fatty rats, exercise partially reverses adverse changes in
PkB/GSK-3b phosphorylation [PMID 14698990]
cinnamon methylhydroxychalcone (MHCP) is a GSK-3b inhibitor which
enhances the actions of insulin and stimulates glucose uptake and
synthesis via PI3K [PMID 11506060;
<http://www.jacn.org/cgi/content/full/20/4/327>;
<http://www.cinnulinpf.com/images/pdfs/MimeticForInsulin.pdf>]; GSK-3b
reduces stable beta-catenin by phosphorylation (see
<http://www.hhmi.org/fuchs/fuchs.pdf>) which is why it has been patented
for hair growth; beta-catenin has to be translocated to the nucleus
where it operates together with LEF-1 to trigger genetic transcription ;
stable beta-catenin, however, might not be enough as it can bind to an
activated androgen receptor and enhance the AR's target gene expression,
which wouldn't be any good for an androgen-driven skin disorder; if it
doesn't crosswire with the AR then beta-catenin can bind to LEF-1/Tcf
and trigger hair follicle development (other necessary factors include
noggin for LEF-1 transcription, sonic hedgehog for migration of stem
cells from the bulge region and costimulation with the Wnt signal - all
or none of which may be partially knocked out in baldness); GSK-3b is
increased in insulin resistance (see notes on zinc and GSK-3b above);
interestingly, several important hair growth pathways also retard
GSK-3b: IGF-I, protein kinase B/Akt (upregulated by minoxidil) and HGF.
For a complete sketch of the pathway, see
<http://www.nature.com/nrc/journal/v3/n10/slideshow/nrc1189_F5.html>; on
the other hand, in prostate cancer GSK-3b inhibits androgen
receptor-driven transciption; Akt expression usually increases as the
cancer progresses thus GSK-3b inhibition may cause greater
androgen-driven cancer growth [PMID 14985354]; another study found that
GSK-3b facillitated androgen signaling and GSK-3b inhibitors resulted in
lower PSA and other androgen-stimulated gene products [PMID 14988390];
histamines are linked to the beta-catenin pathway; in androgenetic
alopecia, hair follicles attract inflammatory infiltrates (including
mast cells), causing inflammation not found in normal scalps [PMID
10494708]; class I MHC is absent in the lower follicle and chondroitin
proteoglycan is present in the sheath and dermal papilla during anagen;
in catagen class I MHC is expressed, macrophases congregate around the
collicle and chondroitin proteoglycans disappears; in telogen the
macrophages disappear [PMID 1714928]