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The cell cycle is a very finely tuned process and responds to the specific needs of any specific tissue or cell. Normally, in an adult tissue, we observe a delicate balance between programmed cell death (apoptosis) and proliferation (cell division) which is responsible for the dynamic steady state. Disruption of this equilibrium by loss of cell cycle control may lead to hyperplasia and eventually to tumor development.
The switch between phases is a hallmark of the cell cycle, and the control mechanisms that restrain cell cycle transition or induce apoptotic signaling pathways after cell stress are known as cell cycle checkpoints. Intrinsic and extrinsic mechanisms act to control and regulate the cell cycle. The intrinsic mechanisms appear at every cycle and the extrinsic mechanisms only act when defects are detected. Loss of these control mechanisms by genetic and epigenetic events results in genomic instability, accumulation of DNA damage, uncontrolled cell proliferation, and eventually tumor development. Cyclin-dependent kinases (Cdks), cyclins, Cdk inhibitors (CKIs), Cdk activator kinases (CAKs), tumor suppressor genes (gatekeepers, caretakers, and landscapers), and oncogenes are the main players in the mammalian cell cycle.
Figure 1. Illustration of the cell cycle and checkpoint control. Courtesy of Richard Wheeler.
Figure 2. Common epigenetic marks found on histone proteins.
Epigenetic changes alter the heritable state of gene expression and chromatin organization without change in DNA sequence. Epigenetic mechanisms regulate all biological processes from the conception to death, by establishing “epigenetic marks” that modulate the expression of genes involved in the regulation of cellular growth, including genome reprogramming during early embryogenesis and gametogenesis, cell differentiation, apoptosis, survival, and genome integrity. However, although these “epigenetic patterns” are established early during development and differentiation, modifications occur all through the life in response to a variety of intrinsic and environmental stimuli, which may lead to disease and cancer. For instance, epigenetic mechanisms such as DNA methylation and histone methylation and deacetylation have been shown to affect the transcription of key genes involved in the regulation of cellular growth, differentiation, apoptosis, transformation, and tumor progression.
Several studies have provided evidences that pRb2/p130 (retinoblastoma related protein) mediates the epigenetic silencing of the estrogen receptor alpha (ER-a) in breast cancer. Moreover, it has been indicated that epigenetic mechanisms controlled by pRb2/p130, as well as epigenetic events affecting Rb2/130 gene expression itself, play an important role in retinoblastoma and lung cancer formation and progression, and can represent key events in the differentiation of normal corneal and conjunctival cells.
These events are mediated by the formation of transcriptionally repressive chromatin states resulting in gene silencing. There are different types of protein complexes capable of altering chromatin, and these may act in a physiological context to modulate DNA accessibility to the transcriptional machinery. For instance, it has been shown that pRb2/p130 can regulate the transcription of ER- and p73 genes by recruiting specific chromatin-modifying enzymes in multimolecular complexes on the ER- and p73 promoters. Furthermore, accumulating evidence indicates that CpG island hypermethylation is an early event in cancer development and may precede the neoplastic process. Methylation-associated silencing has been demonstrated in various genes, including tumor suppressor genes such as p15, p16, p73, VHL, pRb, and MLH1.
Figure 3. How methylation of CpG sites followed by spontaneous deamination leads to a lack of CpG sites in methylated DNA. As a result residual CpG islands are created in areas where methylation is rare, and CpG sites stick (or where C to T mutation is highly detrimentalepigenetic marks found on histone proteins. Courtesy of CFCF.
• Antibodies to Cyclins• Antibodies to Cyclin Dependent Kinases• Antibodies to Tumor Suppressor Proteins
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