CDK6

Official Full Name

cyclin dependent kinase 6

Organism

Homo sapiens

GeneID

1021

Background

The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. Altered expression of this gene has been observed in multiple human cancers. A mutation in this gene resulting in reduced cell proliferation, and impaired cell motility and polarity, and has been identified in patients with primary microcephaly. [provided by RefSeq, Aug 2017]

Synonyms

MCPH12; PLSTIRE;

Bio Chemical Class

Kinase

Protein Sequence

MEKDGLCRADQQYECVAEIGEGAYGKVFKARDLKNGGRFVALKRVRVQTGEEGMPLSTIREVAVLRHLETFEHPNVVRLFDVCTVSRTDRETKLTLVFEHVDQDLTTYLDKVPEPGVPTETIKDMMFQLLRGLDFLHSHRVVHRDLKPQNILVTSSGQIKLADFGLARIYSFQMALTSVVVTLWYRAPEVLLQSSYATPVDLWSVGCIFAEMFRRKPLFRGSSDVDQLGKILDVIGLPGEEDWPRDVALPRQAFHSKSAQPIEKFVTDIDELGKDLLLKCLTFNPAKRISAYSALSHPYFQDLERCKENLDSHLPPSQNTSELNTA

Open

Disease

Brain cancer, Breast cancer, Lung cancer, Psoriasis, Retina cancer, Schizophrenia, Solid tumour/cancer

Approved Drug

5 +

Clinical Trial Drug

9 +

Discontinued Drug

2 +

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Detailed Information

Within the intricate regulatory network of the cell cycle within an organism, CDK6 (Cyclin Dependent Kinase 6) is a key node producing a CMGC family of serine/threonine protein kinase. Key control of G1 phase progression and G1/S transition in the cell cycle, CDK6 is hence crucial for cell proliferation. Its special non-kinase activities affect tissue homeostasis and cell differentiation.

CDK6's Role in the Cell Cycle

Using its interaction with D-type cyclins, CDK6 performs its role by creating an active CDK6-Cyclin D complex. By phosphorylating the retinoblastoma protein (Rb), this complex releases E2F transcription factors to start the production of genes needed for the cell cycle. Ink4 family CDK inhibitors (e.g., p16^INK4A) tightly control CDK6 activity and are hence important for processes of DNA damage repair and cell cycle arrest.

Figure 1 describes how CDK6 functions in cell-cycle progression: in situations of cell-cycle arrest, INK proteins inhibit the kinase activity of CDK4/6–cyclin D complexes, leading to chromatin repression and suppression of gene expression via the activation of the Rb protein, thereby maintaining cell-cycle arrest. Figure 1. CDK6 in cell-cycle progression. (Ji JY, et al., 2010)

Notably, CDK6's role is not limited to cell cycle progression. Research shows it has significant functions in brain development, hematopoietic systems, and immune cell development. For example, the loss of CDK6 impairs the generation of new neurons in the hippocampal dentate gyrus and the subventricular zone; CDK6 also helps maintain the proliferative potential of pancreatic β-cells, supporting insulin secretion.

Tumor-Related Functions

The expression and function of CDK6 are altered in various tumors, often leading to uncontrolled cell cycle regulation. Through binding with Cyclin D, CDK6 drives tumor cell proliferation and plays key roles in chromatin regulation and gene transcription. In cancers like breast cancer and leukemia, overexpression or activation of CDK6 is frequently associated with malignancy and chemotherapeutic resistance.

An important targeted drug for CDK6 is Palbociclib, which inhibits CDK4/6 kinase activity to prevent Rb phosphorylation, thereby inducing cell cycle arrest. In the treatment of advanced breast cancer, Palbociclib has shown significant efficacy in delaying tumor progression. Furthermore, animal studies suggest that inhibiting CDK6 can sensitize PI3K-mutant tumors to PI3K inhibitors, indicating a potential for combination therapies to advance cancer treatment.

Non-Canonical Functions and Transcriptional Regulation

CDK6 also participates in gene expression regulation through kinase-independent mechanisms. Studies have found that CDK6 can directly bind to chromatin, influencing transcriptional activity. For instance, CDK6 modulates the Notch1 signaling pathway in hematopoietic stem cells and tumor cells, affecting cell fate decisions. Additionally, CDK6 cooperates with transcription factors like STAT3 and NF-κB to regulate specific gene expressions through changes in chromatin structure and recruitment of transcription co-activators.

Cyclin D1, as an important partner of CDK6, plays a key role in transcriptional regulation. It not only advances the cell cycle by activating CDK4/6 but also regulates multiple signaling pathways through direct interactions with transcription factors such as STAT and CUX1. In DNA damage repair, Cyclin D1 recruits RAD51 to DNA damage sites, promoting genomic stability. However, overexpression of Cyclin D1 can lead to increased chromosomal instability, further exacerbating cancer progression.

Therapeutic Potential and Challenges of CDK6

Although existing CDK4/6 inhibitors have achieved notable clinical success, they mainly target CDK6's kinase activity and overlook its non-canonical functions. Increasing evidence suggests that CDK6's transcriptional regulatory roles may be even more crucial than its kinase functions in certain contexts. Thus, designing new drugs that can interfere with both CDK6's kinase activity and transcriptional regulation may offer more options for anti-tumor therapy.

The complex interactions between CDK6 and Cyclin D also highlight the need for personalized treatment strategies based on different tissue types and tumor characteristics. For example, different types of Cyclin D (D1, D2, D3) may have tissue-specific roles in CDK6 complexes. Further exploration of these complexes' compositions and their impact on tumorigenesis will help us understand CDK6's dual roles in malignancies, both as a tumor suppressor and a tumor promoter.

References:

Tigan AS, Bellutti F, et al. CDK6-a review of the past and a glimpse into the future: from cell-cycle control to transcriptional regulation. Oncogene. 2016 Jun 16;35(24):3083-91.
Ji JY, Dyson N. Interplay Between Cyclin-Dependent Kinases and E2F-Dependent Transcription. In: Cell Cycle Deregulation in Cancer. 2010 Feb 08; pp. 23-41.
Goel S, Bergholz JS, et al. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022 Jun;22(6):356-372.
Asghar U, Witkiewicz AK, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015 Feb;14(2):130-46.

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