Disease relevance of Cdkn1a

• Cdkn1a, a cell cycle regulator and a candidate for a prostate cancer susceptibility gene, was mapped to its own locus and had polymorphisms, including a 119-bp insertion in the 5' upstream region in BUF rats [1].
• Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase [2].
• The role of G1 cyclin/cdk in Ang II-induced cardiac myocyte hypertrophy by overexpressing cdk inhibitor p21Cip1/Waf1 or p16INK4a was also examined using recombinant adenoviral vectors encoding these genes [3].
• These findings indicate that p53 and p21WAF1/Cip1 are not markers of neuronal death following global cerebral ischemia [4].
• In the ischemia sensitive CA1 region, p53 and p21WAF1/Cip1 messenger RNAs were up-regulated throughout reperfusion following the normothermic insult [4].

High impact information on Cdkn1a

• CO inhibited smooth muscle cell proliferation by activating p38 mitogen-activated protein kinase (MAPK) and p21(Waf1/Cip1) [5].
• These results showed that prostate cancer susceptibility of ACI rats involves at least four loci, and suggested Mme and Cdkn1a as candidates for Pcr1 and Pcs2 [6].
• Thus, Ras-dependent regulation of p18INK4c expression seems to control the ability of rat embryo fibroblasts to proliferate as small multicellular aggregates, whereas p21(Cip1/Waf1) expression seems to regulate the G1-phase arrest induced by the stressful microenvironment found within the inner region of large spheroids [7].
• Sp1 down-regulated p21WAF1/Cip1 expression in SMCs [8].
• Using transient transfection and Western blot analysis, we determined that Ets-1 activates p21WAF1/Cip1 transcription and protein expression [9].

Biological context of Cdkn1a

• It is presently unknown whether the Ets family of transcription factors control p21WAF1/Cip1 gene expression [9].
• Conversely, antisense p21WAF1/Cip1 induced apoptosis in SMCs overexpressing dominant-negative-Sp1. p21WAF1/Cip1 overexpression alone stimulated proliferation and inhibited apoptosis [8].
• Moreover, Rb phosphorylation, which lies immediately downstream of the cyclin D1-Cdk4-p21WAF1/Cip1 complex, was blocked either by Sp1 overexpression or antisense p21WAF1/Cip1 [8].
• Deregulation of p53/p21Cip1/Waf1 pathway contributes to polyploidy and apoptosis of E1A+cHa-ras transformed cells after gamma-irradiation [10].
• Thus, DNA damage of E1A+cHa-ras transformed cells, with a combination of functionally active wild type p53 and inactive p21Cip1/Waf1, contributes to formation of polyploid cells which then die due to apoptosis [10].

Anatomical context of Cdkn1a

• Sp1 inhibits proliferation and induces apoptosis in vascular smooth muscle cells by repressing p21WAF1/Cip1 transcription and cyclin D1-Cdk4-p21WAF1/Cip1 complex formation [8].
• Collectively, these data suggest a model in which NGF-stimulated TrkA-dependent activation of FRS2 supports neurite outgrowth through a mechanism that likely involves the induction of p21(Waf1/Cip1) expression and the arrest of cells at G(1) /S [11].
• Furthermore, mutation in any of these five elements is not sufficient to prevent activation of the p21(WAF1/Cip1) promoter by Sp1 in endothelial cells [12].
• However, the age-related decline in p21(Waf1/Cip1) in the gastric mucosa appears to be independent of p53 status [13].
• We have previously reported that protein kinase C (PKC) signaling can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells, including downregulation of cyclin D1, induction of p21(Waf1/Cip1), and activation of the growth suppressor function of pocket proteins [14].

Associations of Cdkn1a with chemical compounds

• Formation of 8-hydroxydeoxyguanosine and cell-cycle arrest in the rat liver via generation of oxidative stress by phenobarbital: association with expression profiles of p21(WAF1/Cip1), cyclin D1 and Ogg1 [15].
• These results suggest that chrysin exerts its growth-inhibitory effects either through activating p38-MAPK leading to the accumulation of p21(Waf1/Cip1) protein or mediating the inhibition of proteasome activity [2].
• Overexpression of antisense Id3 abrogated the effect of Ang II on the expression of p21(WAF1/Cip1), p27(Kip1), and p53 [16].
• Immunohistochemical staining for BrdU, topoisomerase II-alpha (TopoII), Ki-67 (MIB-5), p21WAF1/Cip1 (p21), and p27Kip1 (p27) was performed [17].
• Nitric oxide (NO) regulates the expression of p21(Waf1/Cip1) in several cell types [18].

Physical interactions of Cdkn1a

• Electrophoretic mobility shift assays revealed that Ets-1 interacts selectively with the -1350GGAA-1347 Ets element in the p21WAF1/Cip1 promoter [9].
• On the other hand, levels of mucosal p21(Waf1/Cip1) (total and the fraction bound to Cdk2), one of the universal inhibitors of Cdks, were found to be lower in aged than in young rats [19].

Regulatory relationships of Cdkn1a

• Previous studies concluded that FB1 repressed cyclin-dependent kinase 2 (CDK2) activity but induced CDK inhibitors p21(Waf1/Cip1), p27(Kip1), and p57(Kip2) in monkey kidney cells (CV-1) [20].
• Ang II, X/XO, and overexpression of sense Id3 downregulated protein expression of p21(WAF1/Cip1), p27(Kip1), and p53 [16].

Other interactions of Cdkn1a

• The stability of mRNA and protein for Cdk2 and p21Waf1/Cip1 in V14-RhoA cells was not significantly different from that of vector-transfected cells [21].
• SMC proliferation inducible by a dominant-negative mutant form of Sp1 was abrogated by antisense strategies targeting p21WAF1/Cip1 [8].
• In contrast, the -1577GGAT-1574 motif mediates basal but not Ets-1 activation of the p21WAF1/Cip1 promoter [9].
• The data suggest that the NO-PKG pathway inhibits AGE-induced proliferation by suppressing activation of JAK2-STAT5 and cyclin D1/cdk4 and induction of p21Waf1/Cip1 [22].
• While initially described as a cyclin kinase inhibitor, p21Waf1/Cip1 has since been shown to have bimodal effects on cell cycle progression and cell proliferation, and evidence is emerging that intracellular localization of this protein plays a role in directing its signaling properties by dictating its interactions with downstream molecules [23].

Analytical, diagnostic and therapeutic context of Cdkn1a

• Co-immunoprecipitation and co-transfection analysis showed that Ets-1 binds p300 and cooperatively activates p21WAF1/Cip1 transcription [9].
• Activation of p53 and its target genes p21(WAF1/Cip1) and PAG608/Wig-1 in ischemic preconditioning [24].
• Changes in selected upregulated genes were confirmed by ratiometric RT-PCR. p21(Cip1/Waf1) was one of the only two genes upregulated in all conditions studied [25].
• Using in situ hybridization, we investigated the hippocampal mRNA expression of p53, and two of its target genes, p21(WAF1/Cip1) and the recently cloned PAG608/Wig-1, in a two-vessel occlusion model of ischemic preconditioning [24].

References