Disease relevance of Cdkn1a

• Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction [1].
• We report here that, similarly to loss of p53, disruption of the p21(WAF1/Cip1) gene results in a markedly increased susceptibility to chemically induced skin carcinoma formation, whereas the number of papillomas is reduced [2].
• It was recently reported that the p53-independent elevation of p21 protein levels is essential in mediating the G(1) arrest resulting from signal transduction events initiated by the crosslinking of membrane IgM on Daudi Burkitt lymphoma cells [3].
• In contrast, higher and sustained levels of proliferation, resulting in myofibroblast hyperplasia and monocytic inflammation, occurred in recovered p21-deficient lungs [4].
• We found that inactivation of p21(WAF1/cip1) significantly increased the frequency and size of intestinal tumors in Muc2 knockout mice and also led to development of more invasive adenocarcinomas [5].

Psychiatry related information on Cdkn1a

• In cell extracts, we found that complementary strand synthesis was inhibited by the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and rescued by the addition of proliferating cell nuclear antigen, arguing for the involvement of DNA polymerase (Pol) delta in the conversion reaction [6].
• Thus, p21 deficiency significantly enhances T cell activation and homeostatic proliferation, and can induce mild autoimmune manifestations at a low incidence without gender bias, but does not in itself generate the full spectrum of lupus-like disease [7].
• We investigated the development of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in AVCN neurons using whole cell patch-clamp techniques during [postnatal day 7 (P7)] and after (P14, P21) this critical period [8].
• Motor coordination was assessed by locomotor activity evaluation of control and experimental pups at P14, P21 and P30 [9].

High impact information on Cdkn1a

• Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation [10].
• Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres [10].
• In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation [10].
• Smad proteins activated by TGF-beta form a complex with FoxO proteins to turn on the growth inhibitory gene p21Cip1 [11].
• p53-mediated increase in cyclin-dependent kinase inhibitor p21(WAF1) protein is thought to be the major mediator of cell cycle arrest after DNA damage [12].

Chemical compound and disease context of Cdkn1a

• Polyomavirus large T antigen coprecipitates with p53 phosphorylated on serine 18 and also with p21Cip1/WAF1 [13].
• The lack of cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) in mice increases renal proximal tubular cell death and enhances sensitivity to acute renal failure produced by the chemotherapeutic agent cisplatin [14].
• Furthermore, in vitro glucose-induced mesangial cell hypertrophy is also associated with an up-regulated expression of p21 [15].
• METHODS: Experimental diabetes mellitus was induced by streptozotocin in mice in which p21 was genetically deleted (p21 -/-) and in wild-type mice (p21 +/+) [15].
• 1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo [16].

Biological context of Cdkn1a

• We suggest that heat-inducible Hsp72 to a larger extent, and constitutive Hsp72 to a lesser extent, together with Cdkn1a may be involved in the protection of M10 cells against heat-induced apoptosis [17].
• The expression of Trp53 and Cdkn1a and the G(1)-phase arrest (one set of data on G(1)-phase delay is included as an example) was not induced by ionizing radiation in these transformed clones; each clone carried a point mutation in Trp53 [18].
• Gadd45a deletion allows another form of genomic instability, gene amplification, when p21 (Cdkn1a gene product) is deleted also [19].
• Radiation-induced cell cycle arrest compromised by p21 deficiency [20].
• However, p21-/- mouse embryo fibroblasts are impaired in their ability to undergo G1 arrest following DNA damage [20].

Anatomical context of Cdkn1a

• Using Casp3-/-Cdkn1a-/- mice, we show that the hyperproliferation of Casp3-/- B cells is abolished when Cdkn1a is also deleted [21].
• Combined use of laser capture microdissection and quantitative reverse transcription-polymerase chain reaction showed that there was a similar change in Cdkn1a expression for the pyramidal cell layer as for total hippocampus [22].
• Northern blot hybridization confirmed the induction of Cdkn1a mRNA in the central nervous system (CNS), and also revealed similar increases in kidney, liver and heart [22].
• The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner [23].
• During postnatal liver development, when transgenic p-21 protein becomes detectable, hepatocyte proliferation is inhibited dramatically [24].

Associations of Cdkn1a with chemical compounds

• Induction of Cdkn1a expression was transient, reaching maximal levels in the CNS 3-6 h after LPS administration, and returning to untreated levels by 24 h [22].
• Cell proliferation was measured by bromodeoxyuridine incorporation following p21(waf1/cip1) silencing with RNAi [25].
• Moreover, p21 is required to a similar extent to maintain cell cycle arrest after either nocodazole treatment or irradiation [26].
• These findings suggest that basal expression of p21 plays a facilitating, proapoptotic role in DCA-induced apoptosis [27].
• Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor [28].

Physical interactions of Cdkn1a

• The promoter assays further confirmed the independency of p53-binding sites in the activation and linked UV-responsive transcriptional regulation of p21 to two Sp1 consensus binding sites within -61 bp of the transcription initiation site [29].
• Conditions that increased the abundance of the D cyclins also increased the abundance of enzymatically active D cyclin-cdk4 complexes in mouse embryo fibroblasts (MEFs) lacking both p27(Kip1) and p21(Cip1) (p27/p21(-/-)) [30].
• A similar ubiquitin ligase complex has been previously shown to be involved in the degradation of a related cyclin-dependent kinase inhibitor, p27Kip1 [31].
• Transient, high-level Ras-expression induces transcriptional activation of p21 mediated by a GC-rich region in p21 promoter -83-54 bp relative to the transcription initiation site containing binding sites for Sp1-family transcription factors [32].
• We show that both the cyclin and cdk2 binding motifs of p21 are crucial for the disruption of this endogenous complex of E2F-p130-cyclin-cdk2 [33].

Enzymatic interactions of Cdkn1a

• Although they had the least injury, p21-deficient mice had the highest levels of hepatic proliferation that correlated with increases in hyperphosphorylated retinoblastoma protein and Cyclin A gene expression [34].

Regulatory relationships of Cdkn1a

• Inactivation of p53 in c-jun (Deltali*) mice abrogated both hepatocyte cell cycle block and increased p21 protein expression [35].
• Surprisingly, p21Waf-1/Cip-1 is induced in the sensory ganglia of Rb-mutant embryos in a p53-independent manner [36].
• The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot [37].
• The same element is also required by p53 to activate the p21(WAF1/Cip1) promoter, although p53 does not bind to it [38].
• Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2-/- mice [5].
• The absence of p21 significantly impaired the enhanced p53-mediated cell-cycle arrest characteristic of super-p53 cells, but did not affect the enhanced apoptosis [39].
• Disruption of SDF-1/CXCR4 signaling inhibited the proliferative response during vascular remodeling in both p21+/+ and p21-/- mice [40].
• Biochemical and genetic data show that oscillation of p21WAF1/CIP1 gene transcription is regulated by the antagonistic activities of the orphan nuclear receptors REV-ERBalpha/beta and RORalpha4/gamma, which are core clock regulators [41].

Other interactions of Cdkn1a

• p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells [23].
• Consistently, liver regeneration was rescued in c-jun (Deltali*) p21 (-/-) double-mutant mice [35].
• Thus, p21 acts as a selective negative regulator of transcription and links the Notch and Wnt signaling pathways in keratinocyte growth control [42].
• p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation [42].
• Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity [1].

Analytical, diagnostic and therapeutic context of Cdkn1a

• Significantly, partial hepatectomy failed to stimulate hepatocytes to proliferate in p21 transgenic animals [24].
• P21(waf1/cip1) messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and Western blot, respectively [25].
• Loss of p53 or gadd45 had a pronounced effect on GGR, while p21 loss had only a marginal effect, determined by measurements of repair synthesis (unscheduled DNA synthesis), by immunoassays to detect removal of UV photoproducts from genomic DNA, and by assays determining strand-specific removal of CPDs from the mouse dhfr gene [43].
• Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 (Waf1) [44].
• For example, absence of the tumor suppressor p27(Kip1), a cyclin-dependent kinase inhibitor (CKI), results in increased body size, hyperplasia of several organs including the testes, and cancer in mice [45].

References