Cyclin D1 Dis-regulation

General Discussion
#1

After extensively reading over blood and urine tests i have found that some show signs of being fast metabolizers, some show slow.
Some show signs of under active 5aR2, some show over.
Some show signs of being estrogen dominant, some have tried to fix this balance and have felt no different.
Basically i am looking for something that has the potential to disrupt everything, from hormone production, to the AR to the degration of hormones.

Background

nar.oxfordjournals.org/content/38/16/5351.full

This study is combined treatment of Finasteride and Quercetin

ncbi.nlm.nih.gov/pubmed/15171697

This could explain why most do alright on finasteride and get worse when quitting, as Finasteride and DHT both inhibit Cyclin D1, there must be a period of time between quiting and the crash where there is no finasteride and no DHT, while 5aR2 regenerates, which would leave Cyclin D1 unregulated.

So that leads into this,

[Size=4]Cyclin D1 Regulates Hepatic Estrogen and Androgen Metabolism[/size]

Discussion

In this study, we provide evidence for a novel interaction between the cell cycle
machinery and sex steroid signaling, whereby cyclin D1 regulates key enzymes involved in the
synthesis and degradation of these hormones. Although previous studies have documented that cyclin D1 controls the activity of ERα and AR through direct binding or by modulating
transcriptional co-regulators, the current experiments suggest that this protein can also regulate the levels of their respective ligands. We found that cyclin D1 affected several different enzymes that play an important role in sex steroid metabolism, suggesting that it may have a coordinated effect on these pathways.

Abnormal regulation of sex steroid metabolism in the setting of liver diseases or resection
is a well-described phenomenon, but the underlying mechanisms have not been established. In
men with cirrhosis, hypogonadism and alterations in the hypothalamic-pituitary axis may explain
some of the features of feminization (40). However, these changes would not likely account for the increased estrogen levels seen in men and post-menopausal women that occur acutely after major liver resection (17, 18, 41), nor the increased levels seen in male mice after PH.

After major hepatectomy, a large number of hepatocytes enter the cell cycle as part of the
regenerative response, and this is accompanied by marked induction of cyclin D1 (15, 34).
Cyclin D1 expression is also elevated in patients with cirrhosis due to ongoing hepatocyte
proliferation that helps to sustain functional liver mass (2, 15, 32). In this study, we provide
evidence that cyclin D1 may account for changes in sex steroid metabolism as follows: (A)
Cyclin D1 regulated the expression of a number of genes involved in steroid synthesis and
degradation in a pattern that would predict increased estrogen and decreased androgen
production in the liver. (B) Short-term cyclin D1 expression in the liver led to increased estrogen levels similar to those seen after PH. © Cyclin D1 promoted expression of estrogen-responsive genes and downregulated androgen-responsive genes in the liver. (D) Cyclin D1 regulated the hepatic activity of key enzymes involved in sex steroid synthesis in a manner that favors increased estrogen and decreased androgen synthesis. (E) PH in mice led to similar changes in gene expression and enzyme activity to those induced by cyclin D1. (F) Knockdown of cyclin D1 expression in the well-differentiated HCC line HuH7 had reciprocal effects on several key genes as compared to cyclin D1 transfection in the liver. While it is highly likely that the hormonal changes seen in the setting of liver disease or PH are regulated by several factors, the data presented here suggest that expression of cyclin D1 in hepatocytes plays an important role.

A handful of prior studies have suggested a link between the cell cycle machinery and
sex steroid metabolism, although a causative role has not been previously established. For
example, in the fetal baboon adrenal gland, cyclin D1 expression decreases during gestation
while 3β-HSD expression increases (14). Treatment of human ovarian cells with the anti-
proliferative agents TGF-β1 and all-trans retinoic acid induces HSD3B1 expression, suggesting
that cell cycle inhibition promotes its expression (36). The data presented here demonstrate that cyclin D1 inhibits 3β-HSD activity (Fig. 3) and down-regulates the expression of key 3β-HSD genes (HSD3B1 and murine HSD3B2, Figs. 1 and 7). In addition, we found that cyclin D1 modulated 17β-HSD mRNA expression and activity in a manner that favors increased estradiol and decreased testosterone synthesis (Figs. 1 and 4). To our knowledge, no previous studies have shown that SRD5A1 varies during the cell cycle, and thus our finding that SRD5A1 was regulated by cyclin D1 in mouse liver and human cancer cells lines is of particular interest.

Previous studies have shown that a central “repressor domain” of cyclin D1 can inhibit
AR function by direct binding to the receptor and by recruiting histone deacetylases to repress
transcription (3). Of note, this mechanism has been established using transfection systems to overexpress cyclin D1, and we are unaware of prior studies looking at knockdown of
endogenous cyclin D1 expression. The data presented here suggest that cyclin D1 may inhibit
AR activity through an additional mechanism, by reducing the availability of androgen ligands.

Although we have not successfully performed SRD5A1 western blot or 5α-reductase enzyme
assays (data not shown), data from mouse liver and human HuH7 cells show that this gene is
inhibited by cyclin D1 expression (Figs. 1 and 6). The down-regulation of SRD5A1 by cyclin D1
does not require the induction of estradiol (Fig. 3) or the activation of cdk4 (Fig. 5). 5α-reductase plays a pivotal role in androgen synthesis, and inhibitors of this enzyme are used for therapy of androgen-responsive prostate cancer. Interestingly, we found that SRD5A1 expression was negligible in cultured HuH7 cells but was induced by DHEA, suggesting that its expression is dependent on steroid ligands. In the presence of DHEA (but not in its absence), cyclin D1 siRNA significantly increased the expression of AR target gene CAR3 (Fig. 7). Thus, modulation of endogenous cyclin D1 levels per se was not sufficient to regulate CAR3, but the combination of a steroid precursor and knockdown of cyclin D1 induced this gene. These data suggest that cyclin D1 may regulate AR activity, in part, by modulating synthesis of androgens at the tissue and cellular level.

In cell culture systems, cyclin D1 has also been shown to regulate the activity of ERα
through at least two different ligand-independent mechanisms (10, 20, 42). The data presented here provide evidence that cyclin D1 also regulates the availability of estradiol, thereby providing an additional potential mechanism by which it can activate ERα. Further study will be required to determine the relative contribution of each mechanism, which may vary between cell types, tissues, and experimental systems. A better understanding of the functional relationship between cyclin D1 and ERα may aid the development of additional therapies for estrogen-responsive malignancies.

The basis for performing the current studies was the unexpected finding that transient
cyclin D1 expression in the liver regulated the expression of a significant number of genes involved in sex steroid metabolism (Table I) (33). We have not yet examined other potentially
relevant enzymes and sex steroids that may be affected by cyclin D1. For example, cyclin D1 downregulated the StARD4 and StARD5 mRNA on the gene array; these encode StAR lipid
transfer proteins that control a rate-limiting step in the biogenesis of steroid hormones.

Similarly, cyclin D1 inhibited expression of GSTA3, which also plays an important role in steroid hormone synthesis. Cyclin D1 also downregulated expression of transcripts encoding glucuronyltransferases (UGT2B1 and UGT2B38) involved in steroid deactivation. Furthermore,
many of these same enzymes are involved in the synthesis of progesterone, which may also be
affected by cyclin D1 expression. Although these findings require further study, they suggest that cyclin D1 significantly regulates these enzyme pathways.

Taken together, our data are consistent with the theme that cyclin D1 regulates hepatic
sex steroid synthesis and degradation at several levels (Fig. 8). Further study is required to
determine the mechanism(s) by which these changes occur, but the findings suggest cyclin D1 may trigger a coordinated response to alter the bioavailability of these ligands in tissues and cells. Relatively little is known about the transcriptional and post-transcriptional mechanisms that regulate key enzymes involved in steroid hormone synthesis (37). Cyclin D1 is known to modulate gene transcription through phosphorylation or direct binding to transcription factors and co-regulators (10), and thus could be inducing a coordinated transcriptional response.

Notably, we found that the cyclin D1-KE mutant, which does not activate cdk4 or promote cell
cycle progression at the time point studied, produced similar changes in serum estradiol and sex steroid metabolism transcript expression. Cdk4-independent actions of cyclin D1 include
transcriptional regulation and modulation of certain metabolic functions (3, 10, 20). Cyclins D2
and D3 also induced serum estrogen levels and regulated key metabolic genes, suggesting that a shared domain may affect the response. The central “repressor domain” of cyclin D1 (which is intact in cyclin D1-KE) is highly homologous to the corresponding regions in cyclins D2 and D3 (3, 13), and thus each of the D-type cyclins may be affecting hormone metabolism through a transcriptional mechanism. However, further investigation will be required to determine the
mechanisms by which cyclin D regulates hormone metabolism in the liver.

In summary, the current studies indicate that cyclin D1 regulates sex steroid metabolism
in the liver and in human cancer cells. Our findings present a potential mechanism for the
increased estrogen and decreased androgen levels seen in males in the setting of liver resection or diseases. Furthermore, these data suggest that cyclin D1 may enhance ERα activity and inhibit AR activity, at least in part, by modulating androgen and estrogen ligands at the tissue or cellular level. These actions of cyclin D1 may be highly relevant to its role in hormone-responsive tissues and cancer.

ajpgi.physiology.org/content/early/2010/03/25/ajpgi.00471.2009.full.pdf

#2

I am not a doctor here or anything like that, but i wonder if going back on a 5aRInhibitor (Which at least 3 people have reported benifits from)and quercetin(or not) then after a couple of days, or when you start feeling benifits (if you do) start supplementing a good dose of DHT and fairly soon after that get off the 5aRInhibitor, and stay on the DHT for a couple of weeks or so(Until 5aR has regenerated).

Interestinly, here is someone who recovered of quercetin, for a brief period of time.

viewtopic.php?f=30&t=1630&p=9146&hilit=quercetin#p9146

#3

nar.oxfordjournals.org/content/38/16/5351.full

biomedcentral.com/1471-2407/8/219

jem.rupress.org/content/early/2011/04/06/jem.20102167.abstract

ncbi.nlm.nih.gov/pubmed/11328859

Assumptions that i am making,

  1. That finasteride played the same role as DHT did before it was inhibited in inhibiting Cyclin D1 expression.
  2. That when finasteride consumption ceased there was a window that existed where there was no finasteride and no DHT.
  3. That when DHT returned it could not proceed in its Cyclin D1 inhibiting duties(these duties are executed via the AR) because the over expressed Cyclin D1 was binding/is binding to the AR, which is interfering with Androgen binding.
#4

I didn’t catch all of what he said but Dr. Jacobs was telling me about an animal study he reviewed where they simulated going on/off a 5ar. He said something about DHT coming back before the systems are ready to handle it. Not sure if it has been published yet. Just thought I’d mention it - sounds similar.

#5

Dexa inhibits Cyclin D1
ncbi.nlm.nih.gov/pubmed/11872634

In animals fed a diet containing a mixture of myoinositol and dexamethasone, a treatment found previously to be effective in preventing the development of tobacco smoke-induced lung tumors in A/J mice, cyclin D1/2 expression was reduced to 30-40% of control levels. A similar decrease in cyclin D1/2 expression was found when animals were fed either myoinositol or dexamethasone alone. Paradoxically, tobacco smoke by itself had a similar effect on cyclin D1/2 expression.

Cannabis modulates cell cycle regulatory genes including Cyclin D1 (not sure if that means it inhibits it or not)
books.google.com/books?id=0QqyOSJEeykC&pg=PA73&lpg=PA73&dq=Cyclin+D1+and+cannabis&source=bl&ots=587AwwaNSe&sig=s4hoXd9Q0oOVYtfWVF09RRVE8CE&hl=en&sa=X&ei=_1NYT93VJ4Ps0gHnv8W7Dw&ved=0CCwQ6AEwAA#v=onepage&q&f=false

Page 72

Just thought I would share since both cannabis and Dexa have been linked to some form of recovery. This level of science is way over my head so if I’m off base sharing this, I apologize.

#6

Thanks Fix this, seems like dexa has mixed results, some have recovered some have got worse, i wonder how many guys took it for 3 weeks +, probably getting pretty dangerous if you take it that long? Maybe ongoing at a low dose is a good idea?

I found this which mentions a higher dose of Resveratrol can reduce cyclin d1, Resveratrol is another thing on this board which has had a little success.

ncbi.nlm.nih.gov/pubmed/11895924

[Size=4]Cyclin D1 is a selective modifier of androgen-dependent signaling and androgen receptor function[/size].

Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ, Aronow BJ, Knudsen KE.
Source
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Abstract

D-type cyclins regulate cellular outcomes in part through cyclin-dependent, kinase-independent mechanisms that modify transcription factor action, and recent in vivo studies showed that cyclin D1 associates with a large number of transcriptional regulators in cells of the retina and breast. Given the frequency of cyclin D1 alterations in cancer, it is imperative to delineate the molecular mechanisms by which cyclin D1 controls key transcription factor networks in human disease. Prostate cancer was used as a paradigm because this tumor type is reliant at all stages of the disease on androgen receptor (AR) signaling, and cyclin D1 has been shown to negatively modulate AR-dependent expression of prostate-specific antigen (KLK3/PSA). Strategies were employed to control cyclin D1 expression under conditions of hormone depletion, and the effect of cyclin D1 on subsequent androgen-dependent gene expression was determined using unbiased gene expression profiling. Modulating cyclin D1 conferred widespread effects on androgen signaling and revealed cyclin D1 to be a selective effector of hormone action. A subset of androgen-induced target genes, known to be directly regulated by AR, was strongly suppressed by cyclin D1. Analyses of AR occupancy at target gene regulatory loci of clinical relevance demonstrated that cyclin D1 limits AR residence after hormone stimulation. Together, these findings reveal a new function for cyclin D1 in controlling hormone-dependent transcriptional outcomes and demonstrate a pervasive role for cyclin D1 in regulating transcription factor dynamics.

ncbi.nlm.nih.gov/pubmed/21212260

#7

To your point of some getting worse and others getting better with Dexa… Does this suggest that HDAC inhibitors may or may not work depending on other factors such as CD138?

debernardis.it/medasq.php?z=sodium%20oxybate%20%5Bmesh%5D%20&abstract=0&quanti=50&highlight=2&dovesiamo=400&daevidenziare=oxybate%20alcohol&azione=Show&free=

“PURPOSE: The purpose of this study was to examine interactions between the proteasome inhibitor bortezomib (Velcade) and the histone deacetylase (HDAC) inhibitors sodium butyrate and suberoylanilide hydroxamic acid in human multiple myeloma (MM) cells that are sensitive and resistant to conventional agents. EXPERIMENTAL DESIGN: MM cells were exposed to bortezomib for 6 h before the addition of HDAC inhibitors (total, 26 h), after which reactive oxygen species (ROS), mitochondrial dysfunction, signaling and cell cycle pathways, and apoptosis were monitored. The functional role of ROS generation was assessed using the free radical scavenger N-acetyl-l-cysteine. RESULTS: Preincubation with a subtoxic concentration of bortezomib markedly sensitized U266 and MM.1S cells to sodium butyrate- and suberoylanilide hydroxamic acid-induced mitochondrial dysfunction; caspase 9, 8, and 3 activation; and poly(ADP-ribose) polymerase degradation; resulting in synergistic apoptosis induction. These events were associated with nuclear factor kappaB inactivation, c-Jun NH(2)-terminal kinase activation, p53 induction, and caspase-dependent cleavage of p21(CIP1), p27(KIP1), and Bcl-2, as well as Mcl-1, X-linked inhibitor of apoptosis, and cyclin D1 down-regulation. The bortezomib/HDAC inhibitor regimen markedly induced ROS generation; moreover, apoptosis and c-Jun NH(2)-terminal kinase activation were attenuated by N-acetyl-l-cysteine. Dexamethasone- or doxorubicin-resistant MM cells failed to exhibit cross-resistance to the bortezomib/HDAC inhibitor regimen, nor did exogenous interleukin 6 or insulin-like growth factor I block apoptosis induced by this drug combination. Finally, bortezomib/HDAC inhibitors induced pronounced lethality in primary CD138(+) bone marrow cells from MM patients, but not in the CD138(-) cell population. CONCLUSIONS: Sequential exposure to bortezomib in conjunction with clinically relevant HDAC inhibitors potently induces mitochondrial dysfunction and apoptosis in human MM cells through a ROS-dependent mechanism, suggesting that a strategy combining these agents warrants further investigation in MM.”,

I have 60 .5 mg Decdan pills that I am debating experimenting with, but I’m a little cautious with the level of severity in sides. Like you said, perhaps just .5mg a day vs 1.5 would be a better route.

#8

Mens Rea took Dexamethasone for 2-3 weeks and I have taken it for about 4 weeks, intermittently.

#9

Fixthis, wow give me minute to work that study out :laughing:

It is starting to get very interseting though,

[Size=4]Cyclin-mediated inhibition of muscle gene expression via a mechanism that is independent of pRB hyperphosphorylation.[/size]

Skapek SX, Rhee J, Kim PS, Novitch BG, Lassar AB.
Source
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

It was recently demonstrated that ectopic expression of cyclin D1 inhibits skeletal muscle differentiation and, conversely, that expression of cyclin-dependent kinase (cdk) inhibitors facilitates activation of this differentiation program (S. S. Rao, C. Chu, and D. S. Kohtz, Mol. Cell. Biol. 14:5259-5267, 1994; S. S. Rao and D. S. Kohtz, J. Biol. Chem. 270:4093-4100, 1995; S. X. Skapek, J. Rhee, D. B. Spicer, and A. B. Lassar, Science 267:1022-1024, 1995). Here we demonstrate that cyclin D1 inhibits muscle gene expression without affecting MyoD DNA binding activity. Ectopic expression of cyclin D1 inhibits muscle gene activation by both MyoD and myogenin, including a mutated form of myogenin in which two potential inhibitory cdk phosphorylation sites are absent. Because the retinoblastoma gene product, pRB, is a known target for cyclin D1-cdk phosphorylation, we determined whether cyclin D1-mediated inhibition of myogenesis was due to hyperphosphorylation of pRB. In pRB-deficient fibroblasts, the ability of MyoD to activate the expression of muscle-specific genes requires coexpression of ectopic pRB (B. G. Novitch, G. J. Mulligan, T. Jacks, and A. B. Lassar, J. Cell Biol., 135:441-456, 1996). In these cells, the expression of cyclins A and E can lead to pRB hyperphosphorylation and can inhibit muscle gene expression. The negative effects of cyclins A or E on muscle gene expression are, however, reversed by the presence of a mutated form of pRB which cannot be hyperphosphorylated. In contrast, cyclin D1 can inhibit muscle gene expression in the presence of the nonhyperphosphorylatable form of pRB. On the basis of these results we propose that G1 cyclin-cdk activity blocks the initiation of skeletal muscle differentiation by two distinct mechanisms: one that is dependent on pRB hyperphosphorylation and one that is independent of pRB hyperphosphorylation.

#10

[Size=4]Effect of Antioxidants, Resveratrol, Quercetin, and N-Acetylcysteine, on the Functions of Cultured Rat Hepatic Stellate Cells and Kupffer Cells[/size]

Abstract

Effects of antioxidants, resveratrol, quercetin, and N-acetylcysteine (NAC) on the functions of cultured rat hepatic stellate cells and Kupffer cells were studied. These compounds dose-dependently suppressed serum-dependent proliferation of stellate cells as determined by [3H]thymidine and 5-bromo-2’-deoxyuridine uptake. Expression of smooth muscle alpha-actin was suppressed by a high dose of resveratrol and quercetin. These phenolic compounds also suppressed inositol phosphate metabolism, tyrosine phosphorylation, and mitogen-activated protein (MAP) kinase activation in platelet-derived growth factor/BB-stimulated stellate cells. Moreover, the phenolic compounds selectively reduced the level of cell cycle protein cyclin D1 in stellate cells. Thus, resveratrol and quercetin might inhibit stellate cell activation by perturbing signal transduction pathway and cell cycle protein expression, whereas mechanism of potent antiproliferative effect of NAC remains to be elucidated. On the other hand, kinetic analysis showed that production of nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) by lipopolysaccharide-stimulated Kupffer cells was strongly inhibited by resveratrol and quercetin but not by NAC. Although expression of messenger RNAs for inducible NO synthase and TNF-alpha was not affected by the phenolic compounds, cellular levels of inducible NO synthase and TNF-alpha secretion were suppressed significantly, indicating the posttranscriptional process of generating these proteins might be affected predominantly by these phenolic compounds. Thus, NAC and these phenolic compounds may have therapeutic potential against liver injury by regulating functions of hepatic stellate cells and Kupffer cells.

ncbi.nlm.nih.gov/pubmed/9581680

[Size=4]Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1 cell cycle arrest in EAC cells.[/size]

Abstract

The objective of this work is to report the antiproliferative effect of P. cupana treatment in Ehrlich Ascites Carcinoma (EAC)-bearing animals. Female mice were treated with three doses of powdered P. cupana (100, 1000 and 2000 mg/kg) for 7 days, injected with 10(5) EAC cells and treated up to day 21. In addition, a survival experiment was carried out with the same protocol. P. cupana decreased the ascites volume (p = 0.0120), cell number (p = 0.0004) and hemorrhage (p = 0.0054). This occurred through a G1-phase arrest (p < 0.01) induced by a decreased gene expression of Cyclin D1 in EAC cells. Furthermore, P. cupana significantly increased the survival of EAC-bearing animals (p = 0.0012). In conclusion, the P. cupana growth control effect in this model was correlated with a decreased expression of cyclin D1 and a G1 phase arrest. These results reinforce the cancer therapeutic potential of this Brazilian plant.

ncbi.nlm.nih.gov/pubmed/20564499

Also found this very interesting, done alot of research on the PPAR’s when i was on my palmitoylethanolamide rampage,

[Size=4]Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation.[/size]

Abstract

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR gamma induces hepatic steatosis, and liganded PPAR gamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR gamma function, transactivation, expression, and promoter activity. PPAR gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPAR gamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR gamma-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1(-/-) fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR gamma ligands of PPAR gamma and PPAR gamma-responsive genes, and cyclin D1(-/-) mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPAR gamma in vivo. The inhibition of PPAR gamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR gamma ligands and mitogenic signals that induce cyclin D1.

ncbi.nlm.nih.gov/pubmed/15713663

PPAR from wiki,

PPAR-G regulates fatty acid storage and glucose metabolism.

Futher more to this thought liganded PPARG promotes adipocyte differentiation.

Also there is a study called this, but you have to buy it.

Could be a reason why some have put on weight, breasts, belly, hips after finateride treatment has finished as stated above cyclin D1 inhibits ligand-induced PPAR gamma function, transactivation, expression, and promoter activity.

I brought some Red clover and want to try it as it is a PPAR-G ligand, but it is also basically estrogen.

ncbi.nlm.nih.gov/pubmed/18724264

Might try a small dose?

So back to inhibiting cyclinD1, in the near future im going to try, all at once, resversatrol, Quercetin (which i know down regulates AR), NAC, Guarana (caffeine free) and marijuana.

Anyone have any thoghts on this?

#11

[Size=4]Cyclin D1 Stimulation of Estrogen Receptor Transcriptional Activity Independent of cdk4†[/size]

Cyclin D1 plays an important role in the development of breast cancer and is required for normal breast cell proliferation and differentiation associated with pregnancy. We show that ectopic expression of cyclin D1 can stimulate the transcriptional activity of the estrogen receptor in the absence of estradiol and that this activity can be inhibited by 4-hydroxytamoxifen and ICI 182,780. Cyclin D1 can form a specific complex with the estrogen receptor. Stimulation of the estrogen receptor by cyclin D1 is independent of cyclin-dependent kinase 4 activation. Cyclin D1 may manifest its oncogenic potential in breast cancer in part through binding to the estrogen receptor and activation of the transcriptional activity of the receptor.

ncbi.nlm.nih.gov/pmc/articles/PMC232384/pdf/175338.pdf

#12

[Size=4]Cyclin D1 Binding to the Androgen Receptor (AR) NH2-Terminal Domain Inhibits Activation Function 2 Association and Reveals Dual Roles for AR Corepression[/size]

Abstract

The androgen receptor (AR) is a member of the nuclear receptor superfamily, the activity of which is critical for the development and progression of prostate cancer. We and others have previously demonstrated that cyclin D1 is a potent corepressor of the AR. Although cyclin D1 is suspected to recruit histone deacetylases to the AR complex, previous studies have demonstrated that this activity alone is insufficient for cyclin D1 function. Here, we uncover a novel, secondary means of cyclin D1-mediated repression, through modulation of AR amino-carboxy terminal interactions. We show that cyclin D1 predominantly binds the N-terminal domain of the AR, dependent on the AR 23FxxLF27 motif. Through this motif, cyclin D1 abrogates the ability of the AR N-terminal domain to interact with the C terminus. Secondary amino-terminal domain sites capable of fostering interaction with the C terminus were refractory to cyclin D1 action, indicating that the ability of cyclin D1 to modulate AR amino-carboxy terminal interactions is specific to 23FxxLF27. Deletion of the N-terminal cyclin D1 binding site severely compromised AR activity (due to loss of FxxLF) but unmasked a repressor action through interaction with the AR C terminus. In summary, these data reveal novel, unexpected mechanisms of cyclin D1 activity and demonstrate that this function of cyclin D1 is critical for AR modulation.

So fixthis may be on to something with the difference in the cd138 gene. Could be the reason why some of us respond to various medications/treatment while others dont.

#13

Or have a negative reaction for that matter. Perhaps there is also a correlation between the sides we experience (some more cognitive and others more sexual) and the gene.

Again, I have a very limited understanding of the context of these studies. I’m not sure that specific gene is related to AR’s or PFS at all, but it was interesting to see how some cells benefited from HDAC inhibitors and others were harmed depending on that gene being + or -. So if I stumbled upon something useful it’s purely by accident. Thanks for starting the thread and all the research you’ve gathered, I wouldn’t even know where to start.

BTW-Is there a way to find out if one is positive or negative for a specific gene?

#14

That’s a pretty interesting little cocktail you have there. I’d be interested to see how you do on it. Although I feel like you’ll probably see some initial benefits bc of the Quercetin (bc of the down regulation, which apparently makes everyone feel better for a bit) What about trying them without that first?

#15

Fixthis that is an idea i may exercise as i was worried about the quercetin, even though there has been positives on the forum from its use.

[Size=4]Dual Control of Neurogenesis by PC3 through Cell Cycle Inhibition and Induction of Math1
[/size]

Abstract

Growing evidence indicates that cell cycle arrest and neurogenesis are highly coordinated and interactive processes, governed by cell cycle genes and neural transcription factors. The gene PC3 (Tis21/BTG2) is expressed in the neuroblast throughout the neural tube and inhibits cell cycle progression at the G1 checkpoint by repressing cyclin D1 transcription. We generated inducible mouse models in which the expression of PC3 was upregulated in neuronal precursors of the neural tube and of the cerebellum. These mice exhibited a marked increase in the production of postmitotic neurons and impairment of cerebellar development. Cerebellar granule precursors of PC3 transgenic mice displayed inhibition of cyclin D1 expression and a strong increase in the expression of Math1, a transcription factor required for their differentiation. Furthermore, PC3, encoded by a recombinant adenovirus, also induced Math1 in postmitotic granule cells in vitro and stimulated the Math1 promoter activity. In contrast, PC3 expression was unaffected in the cerebellar primordium of Math1 null mice, suggesting that PC3 acts upstream to Math1. As a whole, our data suggest that cell cycle exit of cerebellar granule cell precursors and the onset of cerebellar neurogenesis are coordinated by PC3 through transcriptional control of cyclin D1 and Math1, respectively.

[Size=4]Cdk4/CyclinD1 Overexpression in Neural Stem Cells Shortens G1, Delays Neurogenesis, and Promotes the Generation and Expansion of Basal Progenitors[/size]

java-srv1.mpi-cbg.de/publications/getDocument.html?id=8a8182da24bf12ed0124c97f11a20040

So if the cyclin D1 over expression theory was to ring true, brain fog could be explained by altered hormone metabolism and probably more so by the inhibition of neurogenesis.

Anyway, moving on

[Size=4]D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability.[/size]

Abstract

D-type cyclins regulate distinct cellular processes, such as mitotic cell cycle control, differentiation, and transcription. We have previously shown that the D-type cyclins are critical for the androgen-dependent proliferation of prostate cells. Here, we sought to determine whether cyclin D1 directly influences the transactivation potential of the androgen receptor, a transcription factor that strongly influences androgen-dependent proliferation. We found that ligand-mediated transcriptional activation of a physiological target, prostate-specific antigen, by the androgen receptor was inhibited by cyclins D1 and D3. The ability of D-type cyclins to inhibit androgen receptor transactivation was not shared with other cyclins, and cyclin D1 was as effective as dominant negative mutants of the androgen receptor in inhibiting transactivation. This function of cyclin D1 was independent of its role in cell cycle progression and is likely elicited through its ability to form a specific complex with the androgen receptor. These data underscore the various mechanisms through which the androgen receptor is regulated and also point to a negative feedback role for cyclin D1 in controlling androgen-dependent growth.

ncbi.nlm.nih.gov/pubmed/10344732

[Size=4]A central domain of cyclin D1 mediates nuclear receptor corepressor activity.[/size]

Abstract

Regulation of nuclear receptor activity is the focus of numerous ongoing studies to develop novel therapies for the treatment of hormone-related cancer. Although cyclin D1 functions to control the activity of several nuclear receptors, the region(s) of the protein responsible for such transcriptional comodulation remain poorly defined. Herein, we map the region of cyclin D1 required for binding and repression of the androgen receptor (AR) to a central, exclusively alpha-helical domain. Deletion of this domain disrupted AR binding and corepressor activity. Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3. Strikingly, overexpression of this repressor region attenuates cell cycle progression in prostatic adenocarcinoma cells. The requirement of this domain for nuclear receptor repression was conserved with respect to thyroid hormone receptor beta-1, whereas cyclin D1 activation of the estrogen receptor occurred independently of the central region. Together, these data identify a minimal repression module within cyclin D1 and demonstrate that the coactivator and corepressor functions of cyclin D1 are distinct. In addition, our data suggest that properties of the cyclin D1 central domain could be exploited to develop novel prostate cancer therapeutics.

ncbi.nlm.nih.gov/pubmed/15558026

As for vitamin D im fishing here a little,

[Size=4]Cyclin D3 interacts with vitamin D receptor and regulates its transcription activity.[/size]

Abstract

D-type cyclins are essential for the progression through the G1 phase of the cell cycle. Besides serving as cell cycle regulators, D-type cyclins were recently reported to have transcription regulation functions. Here, we report that cyclin D3 is a new interacting partner of vitamin D receptor (VDR), a member of the superfamily of nuclear receptors for steroid hormones, thyroid hormone, and the fat-soluble vitamins A and D. The interaction was confirmed with methods of yeast two-hybrid system, in vitro binding analysis and in vivo co-immunoprecipitation. Cyclin D3 interacted with VDR in a ligand-independent manner, but treatment of the ligand, 1,25-dihydroxyvitamin D3, strengthened the interaction. Confocal microscopy analysis showed that ligand-activated VDR led to an accumulation of cyclin D3 in the nuclear region. Cyclin D3 up-regulated transcriptional activity of VDR and this effect was counteracted by overexpression of CDK4 and CDK6. These findings provide us a new clue to understand the transcription regulation functions of D-type cyclins

Cyclin-dependent kinase 4 (CDK4) is very closely related to cyclin D1

ncbi.nlm.nih.gov/pubmed/11400112

So there is a clear link there.

#16

Two more things some have had success with,

Tribulus terrestris

OBJECTIVE
To investigate the effect of saponins from Tribulus terrestris (STT) on the renal carcinoma cell (786-0) in vitro, and inhibitory mechanisms.
METHOD
Effects of SIT on the cytotoxicity, morphological changes of apoptosis, cell cycle and expression of Bcl-2 protein in the 786-0 were tested respectively by MTT method, Wright and acridine orange stain assay, as well as flow cytometry (FCM).
RESULT
After the 786-0 was treated by STY, it was shown that: 1) A significant cytotoxic effect was observed by MTT assay; 2) Apoptosis-induced was viewed by Wright and acridine orange stain assay; 3) The distribution of 786-0 on S phase was increased; 4.) The expression of Bcl-2 protein and cyclin D1 was decreased.
CONCLUSION
STT can significantly inhibit the growth of 786-0 in vitro, partially, by apoptosis.

ncbi.nlm.nih.gov/pubmed/16245908

And Tamoxifen

Conclusions: Tamoxifen has been shown to inhibit ERα-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ERα-independent cyclin D1 up-regulation. Taken together, our data show that trichostatin A effectively induces cyclin D1 down-regulation through both ERα-dependent and ERα-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.

So the red line brings up an interesting point, we gain resistance to most things we try, and it appears trichostatin A stopped this.

Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs.

#17

How could we get trichostatin A? Do they sell it as a natural supplement?

#18

Its a research only molecule. I dont know how you would get it.

#19

anyway to find out which antifungals have it? maybe nystatin does

#20

mct.aacrjournals.org/content/2/2/151.abstract

I remember that one of the possible side effects is high grade (or something like that) prostate cancer. HDAC recruitment is involved in some cancers. So maybe Propecia caused the recruitment of HDACs.