Function and Organization of the CDKN2A or CDKN2B Locus and Its Role in Human Health and Disease - Essay Example

? A Review of the Function and Organization of the CDKN2A/ CDKN2B Locus and its Role in Human Health and Disease This gene is known to generate several variants, transcript variants which have differences in their specific first exons. Therefore, this implies that the CDKN2A gene has at least three transcript variants which are alternatively spliced. The three spliced variants encode distinct proteins and are eminent. Two of the genes encode isoforms which are structurally related. The structurally related isoforms are known to generally function as CDK4 kinase inhibitors. This leaves only one transcript which is made up of an alternate first exon which is located at 20Kb (Simone Fulda, Heike Allgayer, Helga Rehder, 2009). In the upstream of the remaining part of the gene, the transcript has an alternate ARF (Open Reading Frame) whose function is to specify a protein that is unrelated structurally to other products of other variants. The alternate ARF works as a stabilizer to the tumor suppressor protein that is p53. This is because it is able to interact with the E3 ubiquitin-protein ligase MDM2. Apart from just interaction, it can also seize the E3 ubiquitin-protein ligase MDM2 MDM2which is a responsible for the gradual degradation of the p53. The ARF product encoded by the gene and the CDK inhibitor isoforms, share a similar functionality in the cycle of the cell G1 control, considering the regulatory roles that p53 and CDK4 play in a cell. The gene is usually mutilated and also deleted in several tumors. For this reason, it is known to function as a crucial tumor suppressor gene. Melanomas harbor mutations of somatic nature and deletions that affects CDKN2A locus lying on chromosome 9p21. Taking this into consideration, plus the original identification of germline homozygous-deletions of CDKN2A while the susceptibility traits in familial melanoma kindreds shows a central role for the locus in particularly the melanoma pathogenesis. This locus contains a generally unusual gene organization which gives room for a pair of separate transcripts and as well a corresponding product of gene tumor suppressor to be produced: p19ARF and p16INK4A (Codogno P, 2006). The resulting loss of p16INK4A causes retinoblastoma (RB) tumor suppression activity through the increased activation of CDK4/6-cyclin D1 complex (Menendez S, Khan Z, Coomber DW et al., 2003). On the other hand, the loss of ARF, in human, p14ARF, down modulates the activity of p53 via the MDM2 activation. Therefore, the deletion of the whole of locus achieves inactivation of a pair of critical tumor suppressor pathways: p53 and RB (Esteller M, Tortola S, Toyota M et al., 2000). The pair of distinct proteins, 2, encoded by CDKN2A locus, is exactly specified through the translation of the common 2nd exon in the alternative reading frames (Zhang Y, Xiong Y, 1999). The evident product of alpha transcript, that is p16 (INK4a), is a clearly recognized tumor suppressor that triggers a G1 cell-cycle arrest (Szklarczyk R, Heringa J, Pond SK, Nekrutenko A, 2007). This it achieve by inhibiting phosphorylation of RB protein by the kinases CDK6 and CDK4 which are cyclin-dependent. On the contrary, product of human CDKN2A beta transcript, that is p14 (ARF), activates p53-response manifest in the rather elevated levels of the p21 (CIP1) and MDM2 plus arrest of cell cycle in both the G2/M and G1. As a result of this phenomenon, ARF- induced cell cycle arrest is dependent on p53. This can thus be abrogated through human papilloma virus E6 protein co-expression. P14 (ARF) therefore functions through direct binding to the MDM2 and thus results in stabilization of the collective MDM2 and p53. Equally, the p53 regulates the ARF, p14 expression negatively and an inverse correlation between the p14 expression and the p53 expression which therefore function in particularly the human tumor cell lines. Contrary to this, the p14 (ARF) expression is not in any way involved in the gradual response to DNA damage. The results realized put the ARF in a pathway which is independent, upstream of p53. This also implies that CDKN2A encodes a pair of proteins (2) that are together involved in the tumor suppression. As have been explained, the p14 (ARF) is basically protein in nature. This is in accordance to its composition of amino acid, transcription, including its degradation. It is also transcribed in alternate reading frame of INK4a/ARF locus (CDKN2A), that of a different protein. It is also basic and polyubiquinated the particular N-terminus. The p14 (ARF) accumulates majorly in nucleolus. Here it forms complexes with Mdm2 or NPM which are stable. This kind of interaction exhibited enables the p14 (ARF) to function as a tumor suppressor and this it does by inhibition of the ribosome biogenesis or in the other hand the initiation of p53-dependent cell-cycle arrest and also apoptosis respectively (Bertwistle D, Sherr CJ, 2007). Cancer is commonly associated with the eventual loss and damage of ARF, p53, Rb or INK4a (Cancer Genome Atlas Research, 2008). With the lack of INK4a, Cdk4/6 inappropriately phosphorylates the Rb and this result to the increase of the E2F dependent transcription. Conversely, with the lack of p14 (ARF), Mdm2 also inappropriately inhibits p53 and thus leading to the increased cell survival. In over 50% of all human cancers, the tumor suppressor, which is the p53, is basically mutilated. On the other hand, the HDM2 is usually overexpressed in about 5-10% of all tumors. The INK4a/ARF locus is normally deleted and silenced in several kinds of tumors (ap KL, Li S, Munoz-Cabello AM, et al., 2010). Recently discovered, is the ANRIL. This is a long non-coding RNA which is encoded in the region of chromosome 9p21. This is a region which is prone to polymorphisms which are associated with diseases. As well, the region is usually linked to cardiovascular disease, different kinds of cancers, glaucoma, diabetes and several other medical conditions. It is now evident that the ANRIL regulates the neighboring tumor suppressors CDKN2A/B through the epigenetic mechanism (Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B, 2010). Therefore, it regulates the cell senescence and proliferation. References Cancer Genome Atlas Research, 2008, Comprehensive genomic characterization defines human glioblastoma genes and core pathways, Nature. [1061–8]. Zhang Y, Xiong Y, 1999, Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53, Mol. Cell 3 (5). [579–91]. Szklarczyk R, Heringa J, Pond SK, Nekrutenko A, 2007, Rapid asymmetric evolution of a dual- coding tumor suppressor INK4a/ARF locus contradicts its function, Proc. Natl. Acad. Sci. U.S.A. 104 (31). [12807–12]. Menendez S, Khan Z, Coomber DW et al., 2003, Oligomerization of the human ARF tumor suppressor and its response to oxidative stress, J. Biol. Chem. 278 (21). [18720–9]. Esteller M, Tortola S, Toyota M et al., 2000, Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status, Cancer Res. 60 (1). [129–33]. Codogno P, 2006, Autophagy and caspase-independent cell death: p19ARF enters the game, Dev. Cell 10 (6). [688–9]. Bertwistle D, Sherr CJ, 2007, Regulation of the Arf tumor suppressor in Emicro-Myc transgenic mice: longitudinal study of Myc-induced lymphomagenesis, Blood 109 (2). [792–4]. Cunnington MS, Santibanez Koref M, Mayosi BM, Burn J, Keavney B, 2010, Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression. In Gibson, Greg. PLoS Genet. 6 (4). ap KL, Li S, Munoz-Cabello AM, et al., 2010, Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a, Mol. Cell 38 (5). [662–74]. Simone Fulda, Heike Allgayer, Helga Rehder, 2009, Hereditary Tumors: From Genes to Clinical Consequences. Weinheim: Wiley-VCH, 3-527-32028-8. Read More