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  Indian J Med Microbiol
 

Figure 1: The structure for the human p15INK4b-p14ARF-p16INK4alocus. The genomic structure is well-conserved between human and mice, and thus gene knockout studies have been extensively conducted in mice. The distance between exon 1 β and exon 1α is 19.4 kbp in humans and 12.4 kbp in mice. The exon 1α is 3.8 kbp upstream of exon 2 in humans; 5.2 kbp in mice (from 5' of exon 1α to 5' of exon 2). The ARF-INK4a (CDKN2a) locus is located 11.5 kbp apart from the genomic locus for CDKN2b that encodes for p15INK4b in humans (from 3' of exon 2 for p15INK4bto 5' of exon 1 β). All of p15Ink4b, p19Arf, and p16Ink4agenes act as tumor suppressors as reported by Krimpenfort et al.[8],[29] The DMP1 consensus is located-2.3 kb and-0.31 kb of ARF (shown in red reverse triangles) and-4.04 kb and-1.40 kb of INK4a (pink reverse triangles) in humans. Both of these are Dmp1 target genes although the mode of regulation is different.[30] Pasmant et al. identified a new large antisense noncoding RNA (named ANRIL) to this genomic locus, with a first exon located in the promoter of the p14ARFgene and overlapping the two exons for p15CDKN2b. Expression of ANRIL was simultaneously found with p14ARF both in physiologic and pathologic conditions. Kobayashi et al. found that that p14ARF regulates the stability of the p16INK4a protein in human and mouse cells.[31] Importantly, ARF promoted rapid degradation of p16INK4a protein, which was mediated by the proteasome and more specifically, by interaction of ARF with one of its subunits, regenerating islet-derived protein 3γ. Thus there is a significant crosstalk between ARF and INK4a at the protein level.[31] ULF, MKRN1, and Siva1 are E3 ligases for ARF that accelerates its degradation.[32],[33],[34],[35],[36]

Figure 1: The structure for the human <i>p15</i><sup>INK4b</sup><i>-p14</i><sup>ARF</sup><i>-p16</i><sup>INK4a</sup>locus. The genomic structure is well-conserved between human and mice, and thus gene knockout studies have been extensively conducted in mice. The distance between exon 1 β and exon 1α is 19.4 kbp in humans and 12.4 kbp in mice. The exon 1α is 3.8 kbp upstream of exon 2 in humans; 5.2 kbp in mice (from 5' of exon 1α to 5' of exon 2). The <i>ARF-INK4a</i> (<i>CDKN2a</i>) locus is located 11.5 kbp apart from the genomic locus for <i>CDKN2b</i> that encodes for p15<sup>INK4b</sup> in humans (from 3' of exon 2 for <i>p15</i><sup>INK4b</sup>to 5' of exon 1 β). All of <i>p15</i><sup>Ink4b</sup><i>, p19</i><sup>Arf</sup>, and <i>p16</i><sup>Ink4a</sup>genes act as tumor suppressors as reported by Krimpenfort <i>et al</i>.<sup>[8],[29]</sup> The DMP1 consensus is located-2.3 kb and-0.31 kb of <i>ARF</i> (shown in red reverse triangles) and-4.04 kb and-1.40 kb of <i>INK4a</i> (pink reverse triangles) in humans. Both of these are Dmp1 target genes although the mode of regulation is different.<sup>[30]</sup> Pasmant <i>et al</i>. identified a new large antisense noncoding RNA (named <i>ANRIL</i>) to this genomic locus, with a first exon located in the promoter of the <i>p14</i><sup>ARF</sup>gene and overlapping the two exons for <i>p15</i><sup>CDKN2b</sup>. Expression of <i>ANRIL</i> was simultaneously found with p14<sup>ARF</sup> both in physiologic and pathologic conditions. Kobayashi <i>et al</i>. found that that p14<sup>ARF</sup> regulates the stability of the p16<sup>INK4a</sup> protein in human and mouse cells.<sup>[31]</sup> Importantly, ARF promoted rapid degradation of p16<sup>INK4a</sup> protein, which was mediated by the proteasome and more specifically, by interaction of ARF with one of its subunits, regenerating islet-derived protein 3γ. Thus there is a significant crosstalk between ARF and INK4a at the protein level.<sup>[31]</sup> ULF, MKRN1, and Siva1 are E3 ligases for ARF that accelerates its degradation.<sup>[32],[33],[34],[35],[36]</sup>