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        Epigenetic Marks and Cell Cycle Control


Epigenetic Marks and Cell Cycle Control


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. 




Cell Cycle and Checkpoint Control



Figure 1.  Illustration of the cell cycle and checkpoint control.  Courtesy of Richard Wheeler.


Histone Protein Epigenetic Marks

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. 





CpG Islands



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.


Featured Antibodies for Cell Cycle and Checkpoint Control


• Antibodies to Cyclins
• Antibodies to Cyclin Dependent Kinases
• Antibodies to Tumor Suppressor Proteins




Giordano A, Macaluso M (Ed.). Cancer Epigenetics: Biomolecular Therapeutics for Human Cancer. John Wiley & Sons (2011).
Macaluso M, Fiorentino FP, Miranda F, Montanari M, Russo A, Bagella L, Giordano A. CTCF and BORIS Regulate Rb2/p130 Gene Transcription: A Novel Mechanism and a New Paradigm for Understanding the Biology of Lung Cancer. Mol Cancer Res, 9(2):225-33, 2011
C Bronner, G Fuhrmann,  FL Chedin, M Macaluso, S Dhe-Paganon. The structural domains of UHRF1links the histone code and DNA methylation to ensure faithful epigenetic memory inheritance. Genetics & Epigenetics, 2: 29-36, 2009.
F Fiorentino, C Symonds , M Macaluso , A Giordano.  Senescence and p130/pRb2: A New  Beginning to the End. Cell Research, 19(9):1044-51, 2009.
 M Achour, X Jacq, P Rondé, M Alhosin, C Charlot, T Chataigneau, M Jeanblanc, M Macaluso, A Giordano, AD Hughes, VB. Schini-Kerth, and C Bronner. The interaction of the SRA domain of ICBP90 with an unknown domain of DNMT1 is involved in the regulation of the VEGF gene expression. Oncogene, 27(15):2187-97, 2008.
 M Macaluso, Micaela Montanari , Paul Bart Noto , Valter Gregorio,  Christian Bronner  and Antonio Giordano. Epigenetic modulation of Estrogen Receptor-alpha by pRb Family Proteins: A novel mechanism in breast cancer. Cancer Research 67(16): 7731-7, 2007.
Macaluso M, Montanari M and  Giordano A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzyme. Oncogene, 25(38): 5263-67, 2006.
 Macaluso M, Montanari M, Marshall CM , Gambone A, Tosi GM , Giordano A, and Massaro-Giordano M. Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological cross-talk in human cornea and conjunctiva cells. Cell Death and Differentiation, 13(9): 1515-22, 2006.
 Macaluso M, Montanari M, Cinti C and Giordano A. Modulation of cell cycle components by epigenetic and genetic events. Seminars in Oncology, 32(5): 452-457, 2005.
Macaluso M and Giordano A. How does DNA methylation mark the fate of cells? Tumori, 90:367-372, 2004.
Macaluso M, Cinti C, Russo G, Russo A, Giordano A. pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of Estrogen Receptor- in breast cancer. Oncogene, 22:3511-7, 2003


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