Hi, need to submit a 1000 words essay on the topic A review of the function and organization of the CDKN2A/CDKN2B locus and its role in human health and disease.Download file to see previous pages...

Hi, need to submit a 1000 words essay on the topic A review of the function and organization of the CDKN2A/CDKN2B locus and its role in human health and disease.

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.