UniProt functional annotation for P38936



	UniProt functional annotation for P38936

UniProt code: P38936.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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). {ECO:0000269|PubMed:11595739, ECO:0000269|PubMed:8242751, ECO:0000269|PubMed:9106657}.

Subunit: 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 (PubMed:19536131). Interacts with PSMA3 (PubMed:11350925). Interacts with PCNA (PubMed:11595739, PubMed:18794347, PubMed:18703516, PubMed:8861913). 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 (PubMed:9106657). 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 (PubMed:19445729). Interacts with PIM1 (PubMed:12431783). Interacts with STK11 and NUAK1 (PubMed:25329316). Interacts wih DTL (PubMed:23213251). Interacts with isoform 1 and isoform 2 of TRIM39 (PubMed:23213251). {ECO:0000250|UniProtKB:P39689, ECO:0000269|PubMed:11350925, ECO:0000269|PubMed:11595739, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:18703516, ECO:0000269|PubMed:18794347, ECO:0000269|PubMed:19445729, ECO:0000269|PubMed:19536131, ECO:0000269|PubMed:23213251, ECO:0000269|PubMed:25329316, ECO:0000269|PubMed:8861913, ECO:0000269|PubMed:9106657}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:11463845}. Nucleus {ECO:0000269|PubMed:11463845, ECO:0000269|PubMed:23213251}.

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. {ECO:0000269|PubMed:8242751, ECO:0000269|PubMed:8242752}.

Domain: The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment 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.

Domain: The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.

Ptm: 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. {ECO:0000269|PubMed:10753973, ECO:0000269|PubMed:11463845, ECO:0000269|PubMed:12431783, ECO:0000269|PubMed:16982699, ECO:0000269|PubMed:18794347, ECO:0000269|PubMed:20307683, ECO:0000269|PubMed:25329316}.

Ptm: 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. {ECO:0000269|PubMed:15226418, ECO:0000269|PubMed:23213251}.

Ptm: 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). {ECO:0000250}.

Similarity: Belongs to the CDI family. {ECO:0000305}.

Sequence caution: Sequence=AAB59559.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=AAB59560.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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). {ECO:0000269\|PubMed:11595739, ECO:0000269\|PubMed:8242751, ECO:0000269\|PubMed:9106657}.


Subunit:		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 (PubMed:19536131). Interacts with PSMA3 (PubMed:11350925). Interacts with PCNA (PubMed:11595739, PubMed:18794347, PubMed:18703516, PubMed:8861913). 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 (PubMed:9106657). 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 (PubMed:19445729). Interacts with PIM1 (PubMed:12431783). Interacts with STK11 and NUAK1 (PubMed:25329316). Interacts wih DTL (PubMed:23213251). Interacts with isoform 1 and isoform 2 of TRIM39 (PubMed:23213251). {ECO:0000250\|UniProtKB:P39689, ECO:0000269\|PubMed:11350925, ECO:0000269\|PubMed:11595739, ECO:0000269\|PubMed:12431783, ECO:0000269\|PubMed:18703516, ECO:0000269\|PubMed:18794347, ECO:0000269\|PubMed:19445729, ECO:0000269\|PubMed:19536131, ECO:0000269\|PubMed:23213251, ECO:0000269\|PubMed:25329316, ECO:0000269\|PubMed:8861913, ECO:0000269\|PubMed:9106657}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:11463845}. Nucleus {ECO:0000269\|PubMed:11463845, ECO:0000269\|PubMed:23213251}.
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. {ECO:0000269\|PubMed:8242751, ECO:0000269\|PubMed:8242752}.
Domain:		The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment 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.
Domain:		The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.
Ptm:		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. {ECO:0000269\|PubMed:10753973, ECO:0000269\|PubMed:11463845, ECO:0000269\|PubMed:12431783, ECO:0000269\|PubMed:16982699, ECO:0000269\|PubMed:18794347, ECO:0000269\|PubMed:20307683, ECO:0000269\|PubMed:25329316}.
Ptm:		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. {ECO:0000269\|PubMed:15226418, ECO:0000269\|PubMed:23213251}.
Ptm:		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). {ECO:0000250}.
Similarity:		Belongs to the CDI family. {ECO:0000305}.
Sequence caution:		Sequence=AAB59559.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=AAB59560.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};