Alternative name(s):
CDK-interacting protein 1
Melanoma differentiation-associated protein 6
Short name=MDA-6
p21
Gene names
Name: CDKN1A
Synonyms: CAP20, CDKN1, CIP1, MDA6, PIC1, SDI1, WAF1
Function
May be the important intermediate by which p53/TP53 mediates its role as an inhibitor 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. Ref.1 Ref.17
Subunit structure
Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21 By similarity. Interacts with MKRN1. Interacts with PSMA3. Interacts with PCNA. Component of the ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal domain) with CDK4; the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Binding to CDK2 leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Interacts with PIM1. Ref.17 Ref.18 Ref.20 Ref.24 Ref.26 Ref.28 Ref.29
Subcellular location
Cytoplasm. Nucleus Ref.17 Ref.19 Ref.20.
Tissue specificity
Expressed in all adult tissues, with 5-fold lower levels observed in the brain.
Induction
Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1. Ref.1 Ref.2
Domain
The PIP-box K+4 motif mediates both the interaction with PCNA and the recuitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination. Ref.24 Ref.26
The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex. Ref.24 Ref.26
Post-translational modification
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.
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. Ref.21 Ref.24 Ref.25 Ref.26 Ref.29 Ref.30 Ref.33
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. Ref.15
Sequence similarities
Belongs to the CDI family.
