CCNY

CCNY (Cyclin Y) is a regulatory cyclin that controls cell cycle progression and cytoskeletal organization by activating cyclin-dependent kinase partners, with its functional output dictated by the cell-type-specific availability of those partners (PMID:26305884, PMID:34571979). CCNY binds CDK16 in a mutually stabilizing interaction that elevates CDK16 kinase activity (PMID:26305884), and the CDK16/CCNY complex phosphorylates PRC1 at Thr481 — the first identified substrate of this complex — to maintain PRC1 at its proper subcellular location during interphase and support cell viability (PMID:30992425). This phosphoregulatory axis governs mitotic fidelity: in NSCLC cells, loss of CCNY reduces PRC1 phosphorylation, impairs spindle formation, induces G2/M arrest, and produces multinucleated cells (PMID:40665337). CCNY also promotes G1-phase progression and proliferation in laryngeal carcinoma cells through activation of MEK/ERK signaling and upregulation of cyclin E (PMID:32606977), and its knockdown arrests glioma cell cycle progression (PMID:20441050). CCNY itself is transcriptionally regulated by TET1-mediated 5-hydroxymethylcytosine modification at its promoter CpG islands, linking epigenetic control to its expression in cancer stem cells (PMID:30411496). In terminally differentiated neurons, CCNY is a postsynaptic protein that inhibits long-term potentiation and protects against kainic-acid-induced epilepsy by regulating epilepsy-associated gene expression in hippocampal neurons (PMID:32739426). CCNY is dispensable in tissues lacking its CDK partners — it is not required for spermatogenesis (PMID:26305884) nor for intestinal epithelial proliferation, the latter explained by very low CDK14 expression in those cells (PMID:34571979).

1. 2010 Low

   Established a cellular requirement for CCNY in driving cancer cell proliferation, before any molecular mechanism was known.

   Evidence Lentiviral RNAi knockdown of CCNY in glioma cells with proliferation, colony formation, and cell cycle readouts

   PMID:20441050

   Open questions at the time

   • Single knockdown approach with no pathway placement
   • No CDK partner or substrate identified
   • Off-target RNAi effects not excluded
2. 2015 Medium

   Defined CCNY's biochemical mode of action by showing it binds and activates CDK16, while genetics revealed it is dispensable in some tissues.

   Evidence Co-IP, mass spectrometry phosphosite mapping, kinase activity assays, and Ccny knockout mouse fertility analysis

   PMID:26305884

   Open questions at the time

   • No substrate of the activated CDK16/CCNY complex identified
   • Functional consequences of CDK16 activation in vivo not established
   • Distinction from paralog CCNYL1 leaves CCNY-specific roles incompletely mapped
3. 2018 Medium

   Identified an upstream layer controlling CCNY abundance, linking epigenetic 5hmC marks to its transcription in cancer stem cells.

   Evidence ChIP-PCR for 5hmC at CCNY promoter CpG islands plus TET1 modulation and proliferation assays in renal cancer stem cells

   PMID:30411496

   Open questions at the time

   • Direct demonstration that TET1 binds the CCNY promoter not shown
   • Generality beyond cancer stem cells unknown
   • Effect mediated by a small-molecule (fisetin) rather than genetic TET1 perturbation
4. 2019 High

   Named the first substrate of the CDK16/CCNY complex and placed it in a single pathway controlling cell viability.

   Evidence Analog-sensitive CDK16 (CRISPR-Cas9), proteomics for substrate identification, and epistasis analysis of viability

   PMID:30992425

   Open questions at the time

   • Direct requirement of CCNY (vs CDK16 alone) for PRC1 phosphorylation not isolated in this study
   • Broader substrate repertoire not defined
   • Structural basis of PRC1 Thr481 recognition unknown
5. 2020 Medium

   Extended CCNY function to a CDK-independent-framed proliferative pathway (MEK/ERK/cyclin E) and revealed a distinct neuronal, postsynaptic role.

   Evidence CRISPR knockout/overexpression with MEK/ERK/cyclin E Western blots in laryngeal carcinoma; Ccny knockout mice with kainic acid epilepsy model and hippocampal RNA-seq

   PMID:32606977 PMID:32739426

   Open questions at the time

   • Mechanistic link between CCNY and MEK/ERK activation not resolved
   • Whether neuronal CCNY acts via a CDK partner not established
   • Direct targets among epilepsy-associated genes not distinguished from secondary effects
6. 2021 Medium

   Demonstrated that CCNY function is gated by co-expression of its CDK partner, explaining tissue-specific dispensability.

   Evidence Epithelial-specific conditional Ccny knockout, DSS colitis model, Wnt/proliferation/autophagy assays, and CDK14 expression analysis in IECs

   PMID:34571979

   Open questions at the time

   • Negative result; does not exclude CCNY function in other intestinal contexts
   • CDK14-CCNY complex activity in cells with normal CDK14 not directly tested here
   • Compensation by paralogs not formally excluded
7. 2025 Medium

   Consolidated CCNY's role in mitotic fidelity via PRC1 phosphorylation and showed PRC1 is also independently controlled transcriptionally.

   Evidence CCNY knockdown/inhibition with spindle, cell-cycle, and multinucleation readouts plus xenograft/isograft models in NSCLC; TET2-BACH1 transcriptional axis on PRC1

   PMID:40665337

   Open questions at the time

   • Whether the CCNY-PRC1 axis here is CDK16-dependent not directly shown
   • Relative contributions of phosphorylation vs transcription to PRC1 output not quantified
   • Single-lab in vivo models

• How a single cyclin is partitioned among distinct CDK partners (CDK16, CDK14) and CDK-independent signaling outputs across proliferating, epithelial, and neuronal cell types remains unresolved.
• No structural model of CCNY-CDK complexes in the corpus
• Mechanism linking CCNY to MEK/ERK activation unknown
• Full substrate repertoire beyond PRC1 uncharacterized