CCND1 phospho T286
Function
The protein expressed by the CCND1 gene acts as a regulatory component of the cyclin D1-CDK4 (DC) complex, which phosphorylates and inhibits retinoblastoma (RB) protein family members, including RB1, regulating the cell cycle during the G(1)/S transition. Phosphorylation of RB1 allows the transcription factor E2F to dissociate from the RB/E2F complex, enabling transcription of E2F target genes responsible for G(1) phase progression. In early G(1) phase, it hypophosphorylates RB1. Cyclin D-CDK4 complexes integrate various mitogenic and antimitogenic signals. The protein also serves as a substrate for SMAD3, phosphorylating it in a cell-cycle-dependent manner to repress its transcriptional activity, and forms part of the cyclin D1/CDK4/CDKN1B complex necessary for nuclear translocation and activity. Additionally, it exhibits transcriptional corepressor activity with INSM1 on the NEUROD1 and INS promoters, independent of the cell cycle. This supplementary information is collated from multiple sources and compiled automatically.
Involvement in disease
A chromosomal aberration involving CCND1 may be a cause of B-lymphocytic malignancy, particularly mantle-cell lymphoma (MCL). Translocation t(11;14)(q13;q32) with immunoglobulin gene regions. Activation of CCND1 may be oncogenic by directly altering progression through the cell cycle.
A chromosomal aberration involving CCND1 may be a cause of parathyroid adenomas. Translocation t(11;11)(q13;p15) with the parathyroid hormone (PTH) enhancer.
Multiple myeloma
MM
A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia.
None
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving CCND1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus.
Post-translational modifications
Phosphorylation at Thr-286 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex (PubMed:10766840, PubMed:33854232, PubMed:33854235, PubMed:33854239). It also plays an essential role for recognition by the FBXO31 component of SCF (SKP1-cullin-F-box) protein ligase complex following DNA damage (PubMed:19412162).
Ubiquitinated at Lys-269 by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-286 phosphorylation (PubMed:33854232, PubMed:33854235, PubMed:33854239). The DCX(AMBRA1) complex represents the major regulator of CCND1 stability during the G1/S transition (PubMed:33854232, PubMed:33854235, PubMed:33854239). Also ubiquitinated by a SCF (SKP1-CUL1-F-box protein) ubiquitin-protein ligase complex containing FBXO4 and CRYAB (By similarity). Following DNA damage it is ubiquitinated by some SCF (SKP1-cullin-F-box) protein ligase complex containing FBXO31 (PubMed:19412162). SCF-type ubiquitination is dependent on Thr-286 phosphorylation (PubMed:10766840, PubMed:19412162). Ubiquitinated also by UHRF2 apparently in a phosphorylation-independent manner (PubMed:21952639). Ubiquitination leads to its degradation and G1 arrest. Deubiquitinated by USP2; leading to its stabilization (PubMed:19917254).
Sequence Similarities
Belongs to the cyclin family. Cyclin D subfamily.
Cellular localization
- Nucleus
- Cytoplasm
- Nucleus membrane
- Cyclin D-CDK4 complexes accumulate at the nuclear membrane and are then translocated to the nucleus through interaction with KIP/CIP family members.
Alternative names
BCL1, PRAD1, CCND1, G1/S-specific cyclin-D1, B-cell lymphoma 1 protein, BCL-1 oncogene, PRAD1 oncogene, BCL-1