Alternative titles; symbols
HGNC Approved Gene Symbol: CDKN1A
Cytogenetic location: 6p21.2 Genomic coordinates (GRCh38): 6:36,676,463-36,687,332 (from NCBI)
CDKN1A plays a critical role in the cellular response to DNA damage, and its overexpression results in cell cycle arrest. Upregulation of CDKN1A mRNA and protein following ionizing radiation is dependent on p53 (TP53; 191170), and CDKN1A mediates cell cycle arrest in response to the p53 checkpoint pathway (Bendjennat et al., 2003).
Cyclin-dependent kinase-2 (CDK2; 116953) associates with cyclins A (CCNA2; 123835), D (CCND1; 168461), and E (CCNE1; 123837) and has been implicated in control of the G1 to S phase transition in mammals. Using a yeast 2-hybrid screen to identify CDK2-interacting proteins, Harper et al. (1993) cloned CDKN1A, which they called CIP1. The deduced 164-amino acid protein has a calculated molecular mass of 18.1 kD and contains a bipartite nuclear localization signal. In vitro-translated CIP1 migrated with an apparent molecular mass of 21 kD by SDS-PAGE. Northern blot analysis detected a 2.1-kb transcript in all tissues examined, although 5-fold lower levels were observed in brain. Expression of CIP1 mRNA did not vary during the cell cycle in synchronized normal breast epithelial cells.
The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biologic role as a tumor suppressor. Using a subtractive hybridization approach, El-Deiry et al. (1993) identified CDKN1A, which they called WAF1, as a gene whose induction was associated with wildtype but not mutant p53 gene expression in a human brain tumor cell line. El-Deiry et al. (1993) found that the sequence, structure, and activation by p53 was conserved in rodents. Furthermore, El-Deiry et al. (1993) found that the sequence of CIP1, described by Harper et al. (1993), was identical to that of WAF1.
El-Deiry et al. (1993) mapped the WAF1 gene to chromosome 6p21.2 by fluorescence in situ hybridization. By fluorescence in situ hybridization, Demetrick et al. (1995) also mapped the CDKN1A gene to chromosome 6p21.2.
Huppi et al. (1994) cloned and sequenced a mouse p21 cDNA and established that the gene locus, Waf1, lies proximal to H-2 on chromosome 17.
By immunoprecipitation analysis, Harper et al. (1993) found that CIP1 associated with cyclin A, cyclin D1, cyclin E, and CDK2 in human diploid fibroblasts. They showed that CIP1 was a potent, tight-binding inhibitor of CDKs that could inhibit phosphorylation of the RB1 protein (614041) by several of these complexes. Cotransfection experiments indicated that CIP1 and SV40T antigen functioned in a mutually antagonistic manner to control cell cycle progression in human fibroblasts.
El-Deiry et al. (1993) found that introduction of WAF1 cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, they identified a p53-binding site 2.4 kb upstream of WAF1 coding sequence. The WAF1 promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene.
The WAF1-encoded protein p21 mediates p53 suppression of tumor cell growth. Overexpression of p21 in a tumor cell line suppresses colony formation similar to that resulting from p53 overexpression. To localize the tumor suppression function within the structure of p21, Zakut and Givol (1995) used vectors constructed with systematic truncations of p21 and tested their efficiency in suppressing tumor cell growth. They demonstrated that the N-terminal half of the p21 molecule shows better tumor cell growth suppression than the entire p21 molecule, whereas the C-terminal half of p21 did not show this effect.
Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A-associated CDK2 activity. Levkau et al. (1998) showed that in apoptotic cells the C termini of the CDK inhibitors CDKN1A and CDKN1B (600778) are truncated by specific cleavage. The enzyme involved in this cleavage is CASP3 (600636) and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. These data suggested that CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation.
Overexpression of the receptor tyrosine kinase ERBB2 (164870) confers Taxol resistance in breast cancers (114480). Yu et al. (1998) found that overexpression of ERBB2 inhibits Taxol-induced apoptosis. Taxol activates CDC2 kinase (116940) in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of CDC2 and a dominant-negative mutant of CDC2 blocked Taxol-induced apoptosis in these cells. Overexpression of ERBB2 in MDA-MB-435 cells by transfection transcriptionally upregulates CDKN1A which associates with CDC2, inhibits Taxol-mediated CDC2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In CDKN1A antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, ERBB2 was unable to inhibit Taxol-induced apoptosis. Therefore, CDKN1A participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in ERBB2-overexpressing breast cancer cells.
After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. Bunz et al. (1998) demonstrated that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma-radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.
Raj et al. (2001) reported that adeno-associated virus (AAV) selectively induces apoptosis in cells that lack active p53. Cells with intact p53 activity are not killed but undergo arrest in the G2 phase of the cell cycle. This arrest is characterized by an increase in p53 activity and p21 levels and by the targeted destruction of CDC25C (157680). Neither cell killing nor arrest depends upon AAV-encoded proteins. Rather, AAV DNA, which is single stranded with hairpin structures at both ends, elicits in cells a DNA damage response that, in the absence of p53, leads to cell death.
Myotonic dystrophy 1 (DM1; 160900) is a dominant neuromuscular disorder caused by a trinucleotide (CTG) repeat expansion in the myotonin protein kinase gene (DMPK; 605377). Amack and Mahadevan (2001) showed that DMPK transcripts containing expanded CUG tracts can form both nuclear and cytoplasmic RNA foci. However, transcripts containing neither a CUG expansion alone nor a CUG expansion plus the distal region of the DMPK 3-prime untranslated region RNA affected myogenesis in C2C12 myoblasts. This implies that RNA foci formation and perturbation of any RNA binding factors involved in this process are not sufficient to block myoblast differentiation. RNA analysis of myogenic markers revealed that mutant DMPK 3-prime untranslated region mRNA significantly impeded upregulation of the differentiation factors myogenin (MYOG; 159980) and p21.
Activation of the tumor suppressor p53 (191170) by DNA damage induces either cell cycle arrest or apoptotic cell death. Seoane et al. (2002) demonstrated that MYC (190080) is a principal determinant of this choice. MYC is directly recruited to the p21(CIP1) promoter by the DNA-binding protein MIZ1 (604084). This interaction blocks p21(CIP1) induction by p53 and other activators. As a result MYC switches, from cytostatic to apoptotic, the p53-dependent response of colon cancer cells to DNA damage. MYC does not modify the ability of p53 to bind to the p21(CIP1) or PUMA (605854) promoters, but selectively inhibits bound p53 from activating p21(CIP1) transcription. By inhibiting p21(CIP1) expression MYC favors the initiation of apoptosis, thereby influencing the outcome of a p53 response in favor of cell death.
Hikasa et al. (2003) found p21 downregulation in conjunction with c-fos (164810) upregulation in the lymphocytes of patients with rheumatoid arthritis. Phosphorylation of STAT1 (600555) was also decreased in rheumatoid arthritis lymphocytes. Hikasa et al. (2003) determined that c-fos overexpression led to downregulated phosphorylation and dimerization of STAT1, which in turn downregulated p21 gene expression. They concluded that this regulatory pathway may enhance the proliferation of lymphocytes in rheumatoid arthritis patients.
A t(11;22) translocation results in expression of a fusion protein, EWS (133450)-FLI1 (193067), that is associated with Ewing sarcoma (612219). By electrophoretic mobility shift assays, Nakatani et al. (2003) found that EWS-FLI1 interacted with the ETS consensus sequence within the promoter region of the p21(WAF1) gene. Reporter gene assays indicated that the binding of EWS-FLI1 to at least 2 ETS-binding sites negatively regulated p21(WAF1) promoter activity. EWS-FLI1 also suppressed p21(WAF1) induction by interacting with p300 (602700) and inhibiting its histone acetyltransferase activity.
Bendjennat et al. (2003) found that low doses of ultraviolet (UV) irradiation was associated with p21 degradation in several human and rodent cell lines. Conversely, treatment of cells with a DNA-damaging agent or with gamma irradiation increased p21 levels. High doses of UV irradiation caused rapid cell death with no change in p21 levels. UV-induced p21 degradation was independent of cell transformation and p53 or Rb status of the cell lines, but it required ATR (601215), SKP2 (601436), and p21 ubiquitination. Using a ubiquitination-defective p21 protein, Bendjennat et al. (2003) found that failure to degrade p21 after UV irradiation interfered with nuclear accumulation of PCNA (176740) and compromised DNA repair. Bendjennat et al. (2003) concluded that UV-induced p21 ubiquitination and degradation is part of the cellular response to UV-induced DNA damage.
Ng et al. (2003) showed that human p53RFP (RNF144B; 618869) interacted with p21WAF1 and negatively regulated its expression. p53RFP functioned as an E3 ubiquitin-protein ligase and ubiquitinated p21WAF1 for its degradation, thereby releasing arrested cells from G1 phase and inducing cell death.
Asada et al. (2004) determined that p21 interacts directly with BRAP (604986) in vitro and in vivo, and the interaction requires the C-terminal portion of BRAP and the nuclear localization signal of p21. When cotransfected with BRAP, p21 was expressed in the cytoplasm. Monocyte differentiation of promyelomonocytic cell lines was associated with upregulation of BRAP expression concomitantly with upregulation and cytoplasmic relocalization of p21. Asada et al. (2004) concluded that BRAP plays a role in the cytoplasmic translocation of p21 during monocyte differentiation.
Carreira et al. (2005) showed that MITF (156845) can act as a novel antiproliferative transcription factor able to induce a G1 cell cycle arrest that is dependent on MITF-mediated activation of the p21(Cip1) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between MITF and RB1 potentiates the ability of MITF to activate transcription. Carreira et al. (2005) suggested that MITF-mediated activation of p21(Cip1) expression and consequent hypophosphorylation of RB1 contributes to cell cycle exit and activation of the differentiation program.
Rangarajan et al. (2001) found that Notch1 (190198) activation induced p21 in differentiating mouse keratinocytes, and the induction was associated with the targeting of Rbpjk (147183) to the p21 promoter. Mammucari et al. (2005) showed that Notch1 also activated p21 through a calcineurin (see 114105)-dependent mechanism acting on the p21 TATA box-proximal region. Notch signaling through the calcineurin/NFAT (see 600490) pathway also involved calcipressin (see 602917) and Hes1 (139605).
By yeast 2-hybrid screening of a mouse T-cell lymphoma cDNA library, Jascur et al. (2005) found that p21 interacted with Wisp39 (FKBPL; 617076). Experiments with human and mouse cells revealed that WISP39 interacted simultaneously with p21 and the chaperone HSP90 (see 140571) via different motifs, and that WISP39 functioned as an adaptor to mediate HSP90-dependent p21 stability against proteasome-mediated degradation. WISP39 had no effect on p21 stability in the absence of HSP90. Knockdown of WISP39 via small interfering RNA prevented accumulation of p21 and cell cycle arrest after exposure of cells to 10 Gy of ionizing radiation.
Zhang et al. (2007) noted that hematopoietic stem cells are resistant to human immunodeficiency virus (HIV)-1 infection (see 609423), despite of the presence of CD4 (186940) and CXCR4 (162643), which are involved in viral entry. They found that small interfering RNA-mediated knockdown of p21, but not other CDK inhibitors, altered HIV-1 infection, enhanced HIV-1 replication, and increased HIV-1 integration prior to changes in cell cycling and without altering CD4 and CXCR4 surface expression. Coimmunoprecipitation and Western blot analyses showed that p21 interacted with the HIV-1 integration machinery and appeared to inhibit the ability of HIV-1 to integrate into cellular DNA. Silencing of p21 had no effect on expression of other mediators of resistance to HIV-1 infection. Zhang et al. (2007) concluded that p21 is an endogenous cellular component in stem cells that provides a molecular barrier to HIV-1 infection.
Donner et al. (2007) found that transcriptional activity of the p21 promoter in human cell lines varied in response to distinct p53-activating stimuli. Core Mediator subunits MED1 (PPARBP; 604311) and MED17 (603810) were recruited to the p21 gene regardless of the p53-activating stimuli used. In contrast, 3 subunits of the CDK module of Mediator, CDK8 (603184), MED12 (300188), and cyclin C (CCNC; 123838), were recruited following treatment with nutlin-3, a nongenotoxic drug that activates p53, but not in response to DNA damage induced by ultraviolet light C.
Viale et al. (2009) demonstrated that expression of the cell cycle inhibitor p21 is indispensable for maintaining self-renewal of leukemia stem cells. Expression of leukemia-associated oncogenes in mouse hematopoietic stem cells (HSCs) induced DNA damage and activated a p21-dependent cellular response, which led to reversible cell cycle arrest and DNA repair. Activated p21 is critical in preventing excess DNA damage accumulation and functional exhaustion of leukemic stem cells. Viale et al. (2009) concluded that their data unraveled the oncogenic potential of p21 and suggested that inhibition of DNA repair mechanisms might function as potent strategy for the eradication of the slowly proliferating leukemia stem cells.
Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of ES cell-specific miRNAs with a shared seed sequence (AAGUGC), including several members of the miR290 cluster. Complementary target sequences were found in the 3-prime UTR of the Cdkn1a transcript. All 5 ES cell-specific miRNAs tested (miR291a-3p, miR291b-3p, miR294, miR295, and miR302d) directly targeted the 3-prime UTR of Cdkn1a and inhibited reporter gene expression. Target sites were also identified in the 3-prime UTRs of other inhibitors of the cyclin E-CDK2 pathway, including Rb1, Rbl1 (116957), Rbl2 (180203), and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.
The promoter region of p21 contains 6 GC boxes that are activated by various agents. Koh et al. (2009) found that ZBTB5 (616590) bound the most proximal and overlapping GC boxes 5 and 6 and increased SP1 (189906) binding to these elements. ZBTB5 also bound to 2 distal p53-responsive elements in the p21 promoter and competed with p53 for binding to these elements. ZBTB5 bound SP1 and p53 directly in vitro. The POZ domain of ZBTB5 interacted with corepressor-histone deacetylase complexes, such as BCOR (300485), NCOR (NCOR1; 600849), and SMRT (NCOR2; 600848), resulting in repressive deacetylation of histones H3 (see 602810) and H4 (see 600849) at the p21 proximal promoter. In human cell lines, ZBTB5 stimulated proliferation and cell cycle progression and significantly increased the number of cells in S phase. Koh et al. (2009) concluded that ZBTB5 stimulates cell cycle proliferation by repressing the cell cycle arrest gene p21.
Jeon et al. (2009) found that overexpression of ZBTB2 (616595) in HEK293A cells repressed transcription of p53, ARF (see 600160), and, particularly, the cell cycle arrest gene p21. In contrast, ZBTB2 upregulated expression of HDM2 (MDM2; 164785). ZBTB2 repressed p21 expression via a complex mechanism that involved SP1, p53, GC box-5/6, and 2 distal p53-binding elements. ZBTB2 competed with SP1 to bind the proximal SP1-binding GC box-5/6 and repressed SP1-dependent activation of a p21 reporter. ZBTB2 also bound distal p53-binding elements in the p21 promoter and competed with p53 for binding. Moreover, ZBTB2 interacted directly with p53 and inhibited p53 binding to a p21 reporter. Repression of p21 also involved an interaction of the ZBTB2 POZ domain with the corepressors BCOR, NCOR, and SMRT, resulting in repressive deacetylation of histones H3 and H4 at the p21 proximal promoter.
Lin et al. (2010) showed that although Skp2 inactivation on its own does not induce cellular senescence, aberrant protooncogenic signals as well as inactivation of tumor suppressor genes do trigger a potent, tumor-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic stress-driven senescence neither elicit activation of the p19(Arf)-p53 pathway nor DNA damage, but instead depend on Atf4 (604064), p27 (600778), and p21. Lin et al. (2010) further demonstrated that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten (601728)-deficient cells and tumor regression in preclinical studies. Lin et al. (2010) concluded that their findings provided proof-of-principle evidence that pharmacologic inhibition of Skp2 may represent a general approach for cancer prevention and therapy.
Lee et al. (2012) found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 (608760) failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 to regulate the transcription of the gene encoding the cell cycle inhibitor p21(CDKN1A). With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 (604373) partially rescued postnatal lethality in Atg7 -/- mice. Thus, Lee et al. (2012) concluded that when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways.
Negishi et al. (2014) found that knockdown of the long noncoding RNA APTR (616048) in human cell lines via small interfering RNA reduced cell proliferation, increased the G1 and S populations, and increased mRNA and protein expression of p21. Knockdown of APTR did not inhibit growth in p21 -/- HCT116 cells. Crosslinking and immunoprecipitation analysis revealed that APTR directly bound to multiple sites upstream of the p21 transcriptional start site and recruited the polycomb repressive complex-2 (PRC2) to the p21 promoter region, resulting in histone-3 lys27 trimethylation. The 3-prime end of APTR was sufficient for binding to the PRC2 components EZH2 (601573) and SUZ12 (606245), and the central region of APTR, which includes a complete complementary Alu sequence, was required for recruitment to the p21 promoter region.
Chedid et al. (1994) identified a polymorphism at codon 31 where a single point mutation changed AGC (ser) to AGA (arg) (116899.0001). The change resulted in the loss of a restriction site and gain of another, allowing for rapid screening of the polymorphism. Analysis of genomic DNAs from 50 randomly selected individuals revealed that the basepair substitution occurred with an allelic frequency of 0.14. Transfection studies demonstrated that expression of the arg allele was not associated with loss of tumor suppressor activity. Moreover, screening of 22 tumor DNA samples revealed no association between tumor phenotype and the arg allele.
To study the role of p21 in ATM (607585)-mediated signal transduction pathways, Wang et al. (1997) examined the combined effects of the genetic loss of ATM and p21 on growth control, radiation sensitivity, and tumorigenesis. p21 modifies the in vitro senescent response seen in AT fibroblasts. Wang et al. (1997) found that p21 is a downstream effector of ATM-mediated growth control. However, loss of p21 in the context of an Atm-deficient mouse leads to delay in thymic lymphomagenesis and an increase in acute radiation sensitivity in vivo (the latter principally because of effects on the gut epithelium). Modification of these 2 crucial aspects of the ATM phenotype can be related to an apparent increase in spontaneous apoptosis seen in tumor cells and in the irradiated intestinal epithelium of mice doubly null for Atm and p21. Thus, loss of p21 seems to contribute to tumor suppression by a mechanism that operates via a sensitized apoptotic response.
Partial renal ablation leads to progressive renal insufficiency in mice and is a model of chronic renal failure from diverse causes. Mice develop functional and morphologic characteristics of chronic renal failure after partial renal ablation, including glomerular sclerosis, systemic hypertension, and reduced glomerular filtration. Megyesi et al. (1999) reported that littermates with a homozygous deletion of the p21 gene did not develop chronic renal failure after ablation. The markedly different reactions of the p21 +/+ and p21 -/- animals were not because of differences in glomerular number or degree of renal growth, but rather because of the presence or absence of the normal p21 gene. Although the reaction to the stress of renal ablation was both hyperplastic and hypertrophic in the presence of a functional p21 gene, it appeared that the absence of the p21 gene may induce a more hyperplastic reaction because proliferating cell nuclear antigen (PCNA; 176740) expression, a marker of cell cycle progression, in the renal epithelium of the remnant kidney was more than 5 times greater in the p21 -/- mice than in the p21 +/+ animals. Because p21 is a potent inhibitor of the cell cycle, Megyesi et al. (1999) speculated that p21 regulates the balance between hyperplasia and hypertrophy after renal ablation. They proposed that this change in response inhibits the development of chronic renal failure. The studies suggested that controlling p21 function may ameliorate or even prevent progressive end-stage renal disease. Al-Awqati and Preisig (1999) commented on the significance of these findings.
Relative quiescence is a defining characteristic of hematopoietic stem cells, while their progeny have dramatic proliferative ability and inexorably move toward terminal differentiation. The quiescence of stem cells has been conjectured to be of critical biologic importance in protecting the stem cell compartment, which Cheng et al. (2000) directly assessed using mice engineered to be deficient in p21. In the absence of p21, hematopoietic stem cell proliferation and absolute number were increased under normal homeostatic conditions. Exposing the animals to cell cycle-specific myelotoxic injury resulted in premature death due to hematopoietic cell depletion. Further, self-renewal of primitive cells was impaired in serially transplanted bone marrow from p21 -/- mice, leading to hematopoietic failure. Cheng et al. (2000) concluded that p21 is the molecular switch governing the entry of stem cells into the cell cycle, and in its absence, increased cell cycling leads to stem cell exhaustion. Under conditions of stress, restricted cell cycling is crucial to prevent premature stem cell depletion and hematopoietic death.
Salvador et al. (2002) showed that GADD45A (126335) is a negative regulator of T-cell proliferation because, compared with wildtype cells, T cells, but not B cells, from Gadd45a-deficient mice had a lower threshold of activation and proliferated to a greater extent. The mutant mice were also prone to a systemic lupus erythematosus (152700)-like condition characterized by high titers of anti-dsDNA, anti-ssDNA, and antihistone antibodies, severe hematologic disorders, autoimmune glomerulonephritis, and premature death. In mice lacking both Gadd45a and p21, the development of autoimmunity was greatly accelerated.
Barboza et al. (2006) noted that the human p53 R175P mutation is deficient in apoptosis but retains partial cell cycle arrest function. They developed a line of mice homozygous for the corresponding mouse mutation (R172P) on a p21-null background and found that loss of p21 completely abolished cell cycle arrest and accelerated tumor onset. Cytogenetic examination of double-mutant sarcomas and lymphomas revealed aneuploidy and chromosomal aberrations that were absent in the single p53-mutant malignancies.
Telomere shortening limits the proliferative life span of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21, encoded by the CDKN1A gene. Telomere shortening in response to mutation of the gene encoding telomerase (TERC; 602322) is associated with impaired organ maintenance and shortened life span in humans and in mice. Roy Choudhury et al. (2007) showed that deletion of p21 prolongs the life span of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improves the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. These results were experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo but can limit longevity at the organismal level.
Since CDKN1A probably mediated the growth suppression effects of p53 by arresting the cell cycle at the G1/S checkpoint and inducing apoptosis, Mousses et al. (1995) sought mutations in the gene in primary human tumors. Unique or acquired somatic mutations were not observed in primary breast and carcinoma specimens; however, 2 common variants were identified. The variants were not unique to tumors, as 10.7% of normal individuals exhibited the variants. Nonetheless, the frequency of the variants in tumors with wildtype p53 (20.4%) was significantly greater (P = 0.05) than in normal DNAs. In contrast, the frequency of the variants (4.1%) was found to be significantly lower in tumors with p53 mutations (p = 0.006). These data suggested to the authors that occurrence of the variants may have a direct effect on tumor development and may, in some cases, be incompatible with p53 mutations. One of the variants found by Mousses et al. (1995) was an AGC-to-AGA substitution in codon 31 (ser31-to-arg), which had been observed previously by Chedid et al. (1994). The other was a C-to-T change in the 3-prime untranslated region of the CDKN1A gene 20 bp following the stop codon. Sjalander et al. (1996) found an increased frequency of the p21 codon 31ARG allele in lung cancer patients, especially in comparison with patients with chronic obstructive pulmonary disease (COPD); p = 0.004. Thus allelic variants of both p53 and its effector protein p21 may have an influence on lung cancer.
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