Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uncontrolled cellular proliferation is the hallmark of human malignant brain tumors. Their growth proceeds inexorably, in part because their cellular constituents have an altered genetic code that enables them to evade the checks and balances of the normal cell cycle. Recently, a number of major advances in molecular biology have led to the identification of several critical genetic and enzymatic pathways that are disturbed in cancer cells resulting in uncontrolled cell cycling. We now know that the progression of a cell through the cell cycle is controlled in part by a series of protein kinases, the activity of which is regulated by a group of proteins called cyclins. Cyclins act in concert with the cyclin-dependent kinases (CDKs) to phosphorylate key substrates that facilitate the passage of the cell through each phase of the cell cycle. A critical target of cyclin-CDK enzymes is the retinoblastoma tumor suppressor protein, and phosphorylation of this protein inhibits its ability to restrain activity of a family of transcription factors (E2F family), which induce expression of genes important for cell proliferation. In addition to the cyclins and CDKS, there is an emerging family of CDK inhibitors, which modulate the activity of cyclins and CDKs. CDK inhibitors inhibit cyclin-CDK complexes and transduce internal or external growth-suppressive signals, which act on the cell cycle machinery. Accordingly, all CDK inhibitors are candidate tumor suppressor genes. It is becoming clear that a common feature of cancer cells is the abrogation of cell cycle checkpoints, either by aberrant expression of positive regulators (for example, cyclins and CDKs) or the loss of negative regulators, including p21Cip1 through loss of function of its transcriptional activator p53, or deletion or mutation of p16ink4A (multiple tumor suppressor 1/CDKN2) and the retinoblastoma tumor suppressor protein. In this review, we describe in detail our current knowledge of the normal cell cycle and how it is disturbed in cancer cells. Because there have now been a number of recent studies showing alterations in cell cycle gene expression in human brain tumors, we will review the derangements in both the positive and negative cell cycle regulators that have been reported for these neoplasms. A thorough understanding of the molecular events of the cell cycle may lead to new opportunities by which astrocytoma cell proliferation can be controlled either pharmacologically or by gene transfer techniques.
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PMID:Current concepts in neuro-oncology: the cell cycle--a review. 914 59

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent for adult T-cell leukemia (ATL) and various human myopathies/neuropathies. HTLV-I encodes a 40 kDa phosphoprotein, Tax, which has been implicated in cellular transformation. In similarity with several other oncoproteins such as Myc, Jun, and Fos, Tax is a transcriptional activator. How Tax mechanistically dysregulates the cell cycle remains unclear. Recent findings from us and others have shown that Tax targets key regulators of G1/S and M progression such as p16INK4a, cyclin D1, cyclin D3-cdk, and the mitotic spindle checkpoint apparatus. Thus, Tax influences the progression of cells in various phases of the cell cycle. In this regard, we will discuss three distinct mechanisms through which Tax affects cell-cycling: a) through direct association Tax can abrogate the inhibitory function of p16INK4a on the G1-cdks, b) Tax can also directly influence cyclin D-cdk activities by a protein-protein interaction, and c) Tax targets the HsMAD1 mitotic spindle-assembly checkpoint protein. Through these varied routes, the HTLV-I oncoprotein dysregulates cellular growth controls and engenders a proclivity of cells toward a loss of DNA-damage surveillance.
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PMID:HTLV-I Tax and cell cycle progression. 1074 Aug 23

The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.
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PMID:Ink4a/Arf expression is a biomarker of aging. 1552 Aug 54

Senescence, the state of permanent cell cycle arrest, has been associated with endothelial cell dysfunction and atherosclerosis. The cyclin dependent kinase inhibitors p21(CIP1/WAF1) and p16(INK4a) govern the G(1)/S cell cycle checkpoint and are essential for determining whether a cell enters into an arrested state. The homeodomain transcription factor MEOX2 is an important regulator of vascular cell proliferation and is a direct transcriptional activator of both p21(CIP1/WAF1) and p16(INK4a). MEOX1 and MEOX2 have been shown to be partially functionally redundant during development, suggesting that they regulate similar target genes in vivo. We compared the ability of MEOX1 and MEOX2 to activate p21(CIP1/WAF1) and p16(INK4a) expression and induce endothelial cell cycle arrest. Our results demonstrate for the first time that MEOX1 regulates the MEOX2 target genes p21(CIP1/WAF1) and p16(INK4a). In addition, increased expression of either of the MEOX homeodomain transcription factors leads to cell cycle arrest and endothelial cell senescence. Furthermore, we show that the mechanism of transcriptional activation of these cyclin dependent kinase inhibitor genes by MEOX1 and MEOX2 is distinct. MEOX1 and MEOX2 activate p16(INK4a) in a DNA binding dependent manner, whereas they induce p21(CIP1/WAF1) in a DNA binding independent manner.
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PMID:Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells. 2220

Ambient air particulate matter (PM) induces senescence in human skin cells. However, the underlying mechanisms remain largely unknown. We investigated how epigenetic regulatory mechanisms participate in cellular senescence induced by PM with a diameter <2.5 (PM2.5) in human keratinocytes and mouse skin tissues. PM2.5-treated cells exhibited characteristics of cellular senescence. PM2.5 induced a decrease in DNA methyltransferase (DNMT) expression and an increase in DNA demethylase (ten-eleven translocation; TET) expression, leading to hypomethylation of the p16INK4A promoter region. In addition, PM2.5 led to a decrease in polycomb EZH2 histone methyltransferase expression, whereas the expression of the epigenetic transcriptional activator MLL1 increased. Furthermore, binding of DNMT1, DNMT3B, and EZH2 to the promoter region of p16INK4A decreased in PM2.5-treated keratinocytes, whereas TET1 and MLL1 binding increased, leading to decreased histone H3 lysine 27 trimethylation (H3K27Me3) and increased H3K4Me3 in the promoter of p16INK4A. PM2.5-induced senescence involved aryl hydrocarbon receptor (AhR)-induced reactive oxygen species (ROS) production. ROS scavenging dampened PM2.5-induced cellular senescence through regulation of DNA and histone methylation. Altogether, our work shows that skin senescence induced by environmental PM2.5 occurs through ROS-dependent the epigenetic modification of senescence-associated gene expression. Our findings provide information for the design of preventive and therapeutic strategies against skin senescence, particularly in light of the increasing problem of PM2.5 exposure due to air pollution.
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PMID:Particulate matter-induced senescence of skin keratinocytes involves oxidative stress-dependent epigenetic modifications. 3155 8