Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The control and alteration of key regulatory enzymes is a determinant of the reactions and pathways of intermediary metabolism in mammalian cells. An important mechanism in the metabolic control is the hormonal regulation of the genes associated with the transcription and the biosynthesis of these key enzymes. The secretory epithelial cells of the prostate gland of humans and other animals possess a unique citrate-related metabolic pathway regulated by testosterone and prolactin. This specialized hormone-regulated metabolic activity is responsible for the major prostate function of the production and secretion of extraordinarily high levels of citrate. The key regulatory enzymes directly associated with citrate production in the prostate cells are mitochondrial aspartate aminotransferase, pyruvate dehydrogenase, and mitochondrial aconitase. Testosterone and prolactin are involved in the regulation of the corresponding genes associated with these enzymes (which we refer to as "metabolic genes"). The regulatory regions of these genes contain the necessary response elements that confer the ability of both hormones to control gene transcription. In this report, we describe the role of protein kinase c (PKC) as the signaling pathway for the prolactin regulation of the metabolic genes in prostate cells. Testosterone and prolactin regulation of these metabolic genes (which are constitutively expressed in all mammalian cells) is specific for these citrate-producing cells. We hope that this review will provide a strong basis for future studies regarding the hormonal regulation of citrate-related intermediary metabolism. Most importantly, altered citrate metabolism is a persistent distinguishing characteristic (decreased citrate production) of prostate cancer (PCa) and also (increased citrate production) of benign prostatic hyperplasia (BPH). An understanding of the role of hormonal regulation of metabolism is essential to understanding the pathogenesis of prostate disease. The relationships described for the regulation of prostate cell metabolism provides insight into the mechanisms of hormonal regulation of mammalian cells in general.
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PMID:Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. 1219 95

PTEN (phosphatase and tensin homologue deleted on chromosome-10), a dual specificity phosphatase, is a tumor suppressor gene whose inactivation has been associated with many different types of cancer including prostate cancer. Prostate adenocarcinoma is one of the most commonly diagnosed malignancies afflicting the male population in both the United States and Europe. The frequency of PTEN inactivation appears to increase during the progression of prostatic cancer. The physical loss of the PTEN genetic locus in prostate cancer progression has been well characterized, however the molecular implication of this loss of PTEN remains enigmatic. The purpose of this review is to describe the functional role of PTEN in the molecular pathogenesis of prostatic disease. We review the function of PTEN discussing its association with the phosphoinositol 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signal transduction pathways. Additionally, we discuss the role of PTEN in the regulation of apoptotic pathways involving the anti-apoptotic gene bcl-2 and the pro-apoptotic ligand TRAIL. We also review the mechanisms that can lead to the loss of PTEN function. We describe genetic inactivation including loss of heterozygosity, haploinsufficiency and mutation. We conclude by outlining epigenetic loss including methylation, post-translational modifications and oxidative stress.
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PMID:The role of PTEN in the progression and survival of prostate cancer. 1271 46

Activation of the PI3K/Akt signaling cascade is often associated with advanced forms of prostatic carcinoma (CaP). This is likely explained by the common loss of the PTEN gene in a majority of CaP patients. Conversely, activation of the Raf/MEK/ERK pathway is seldom linked with prostatic disease. The interplay between these two pathways in advanced CaP has not been established. The following manuscript demonstrates that Akt can directly associate with Raf-1 causing its inactivation via phosphorylation of a negative regulatory residue (serine 259). Inhibition of PI3K with either LY294002 and wortmannin was sufficient to cause upregulation of ERK activity as measured by immunoblotting. Prolonged treatment with two commonly-used chemotoxic compounds, doxorubicin and paclitaxel, caused increased activation of ERK in PTEN-positive DU145 cells, but not PTEN-negative PC3 cells. Others have reported that ERK activation is essential for drug-induced death, which, when combined with these data, supports the notion that Akt plays an integral role in the response of prostate cancer cells to chemotherapeutic drugs. These results demonstrate that, in prostate cancer cells, the efficacy of chemotherapy may be limited by its effects on the intracellular signaling pathways found within the cell. The genotype of the tumor must be considered for an effective response to these and other antineoplastic drugs.
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PMID:Akt inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells. 1825 41