CDKN1A

This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene.

Cyclin Dependent Kinase Inhibitor 1A

May be involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739).
Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest (PubMed:9106657).

Animal organ regeneration Source: Ensembl
Cell cycle arrest Source: BHF-UCL
Cellular response to amino acid starvation Source: UniProtKB
Cellular response to DNA damage stimulus Source: BHF-UCL
Cellular response to extracellular stimulus Source: BHF-UCL
Cellular response to gamma radiation Source: Ensembl
Cellular response to heat Source: Ensembl
Cellular response to ionizing radiation Source: BHF-UCL
Cellular response to UV-B Source: UniProtKB
Cellular senescence Source: BHF-UCL
Cytokine-mediated signaling pathway Source: Reactome
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Source: BHF-UCL
DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator Source: Ensembl
G1/S transition of mitotic cell cycle Source: BHF-UCL
G2/M transition of mitotic cell cycle Source: BHF-UCL
Granulocyte differentiation Source: Reactome
Heart development Source: BHF-UCL
Intestinal epithelial cell maturation Source: Ensembl
Intrinsic apoptotic signaling pathway Source: ProtInc
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: Ensembl
Mitotic cell cycle arrest Source: BHF-UCL
Mitotic G2 DNA damage checkpoint Source: UniProtKB
Negative regulation of apoptotic process Source: Ensembl
Negative regulation of cardiac muscle tissue regeneration Source: BHF-UCL
Negative regulation of cell growth Source: BHF-UCL
Negative regulation of cell population proliferation Source: BHF-UCL
Negative regulation of cyclin-dependent protein kinase activity Source: CAFA
Negative regulation of DNA biosynthetic process Source: UniProtKB
Negative regulation of G1/S transition of mitotic cell cycle Source: MGI
Negative regulation of gene expression Source: Ensembl
Negative regulation of phosphorylation Source: BHF-UCL
Negative regulation of protein binding Source: UniProtKB
Negative regulation of vascular associated smooth muscle cell proliferation Source: BHF-UCL
Positive regulation of B cell proliferation Source: Ensembl
Positive regulation of fibroblast proliferation Source: BHF-UCL
Positive regulation of programmed cell death Source: Ensembl
Positive regulation of protein kinase activity Source: MGI
Positive regulation of reactive oxygen species metabolic process Source: BHF-UCL
Protein import into nucleus Source: Ensembl
Protein stabilization Source: Reactome
Ras protein signal transduction Source: BHF-UCL
Regulation of cell cycle G1/S phase transition Source: UniProtKB
Regulation of cyclin-dependent protein serine/threonine kinase activity Source: ProtInc
Regulation of transcription by RNA polymerase II Source: Reactome
Regulation of transcription initiation from RNA polymerase II promoter Source: Reactome
Replicative senescence Source: Ensembl
Response to arsenic-containing substance Source: Ensembl
Response to corticosterone Source: Ensembl
Response to drug Source: Ensembl
Response to hyperoxia Source: Ensembl
Response to organonitrogen compound Source: Ensembl
Response to toxic substance Source: Ensembl
Response to X-ray Source: Ensembl
Stress-induced premature senescence Source: BHF-UCL
Tissue regeneration Source: Ensembl
Wound healing Source: Ensembl

Nucleus; Cytoplasm

Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA. Phosphorylation at Ser-114 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex. Phosphorylation of Thr-145 by PIM2 enhances CDKN1A stability and inhibits cell proliferation. Phosphorylation of Thr-145 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Thr-80 by LKB1 and at Ser-146 by NUAK1 leads to its degradation.
Ubiquitinated by MKRN1; leading to polyubiquitination and 26S proteasome-dependent degradation. Ubiquitinated by the DCX(DTL) complex, also named CRL4(CDT2) complex, leading to its degradation during S phase or following UV irradiation. Ubiquitination by the DCX(DTL) complex is essential to control replication licensing and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation.
Acetylation leads to protein stability. Acetylated in vitro on Lys-141, Lys-154, Lys-161 and Lys-163. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1 (By similarity).