CDK4

Official Full Name

cyclin dependent kinase 4

Organism

Homo sapiens

GeneID

1019

Background

The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

Synonyms

CMM3; PSK-J3;

Bio Chemical Class

Kinase

Protein Sequence

MATSRYEPVAEIGVGAYGTVYKARDPHSGHFVALKSVRVPNGGGGGGGLPISTVREVALLRRLEAFEHPNVVRLMDVCATSRTDREIKVTLVFEHVDQDLRTYLDKAPPPGLPAETIKDLMRQFLRGLDFLHANCIVHRDLKPENILVTSGGTVKLADFGLARIYSYQMALTPVVVTLWYRAPEVLLQSTYATPVDMWSVGCIFAEMFRRKPLFCGNSEADQLGKIFDLIGLPPEDDWPRDVSLPRGAFPPRGPRPVQSVVPEMEESGAQLLLEMLTFNPHKRISAFRALQHSYLHKDEGNPE

Open

Disease

Brain cancer, Breast cancer, Liposarcoma, Lung cancer, Malignant haematopoietic neoplasm, Mature B-cell lymphoma, Prostate cancer, Psoriasis, Retina cancer, Schizophrenia, Solid tumour/cancer

Approved Drug

5 +

Clinical Trial Drug

17 +

Discontinued Drug

5 +

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Detailed Information

Specifically the G1-S phase transition, the cyclin-dependent kinase 4 (CDK4) gene codes a serine/threonine kinase that is very essential in controlling the cell cycle. Together with D-type cyclins, CDK4 forms a complex that controls S phase entrance and slows down G1 phase advancement. The retinoblastoma (Rb) protein dissociates from the E2F transcription factor and requires this kinase for phosphorylation, therefore enabling the production of genes needed for DNA replication and cell cycle advancement. Different malignancies have been linked to the dysregulation of CDK4, and mutations in associated proteins including D-type cyclins, Rb, and the CDK inhibitor p16INK4a. We investigate in this review the importance of CDK4 in cancer and its possible therapeutic target value.

CDK4 and Cell Cycle Regulation

Members of the cyclin-dependent kinase family, CDK4 control important changes in the cell cycle in concert with cyclins. In particular, CDK4 forms a complex with cyclin D that phosphorylates Rb, a fundamental negative regulator of the cell cycle. Rb phosphorylated by CDK4 releases E2F transcription factors, which are thereafter free to trigger the expression of genes required for the change from the G1 phase to the S phase. Cyclin D and the CDK inhibitors closely control CDK4 activity; especially p16INK4a, which stops CDK4 from phosphorylating Rb, therefore stopping cell cycle progression.

CDK4 and Cancer Development

Whether resulting from abnormalities in the gene itself or its regulating systems, disruption of CDK4 activity may cause unchecked cell proliferation and cancer formation. Tumorigenesis is often correlated with either overexpression in cyclin D, p16INK4a, or Rb or mutations in cyclin D. This is especially clear in cancers such as melanoma, breast cancer, and gastrointestinal tumors where CDK4 is crucial in stimulating cell division and encouraging tumor growth.

Elevated CDK4 expression has been linked in many studies to a worse prognosis in cancer patients. Particularly in certain malignancies, including esophageal squamous cell carcinoma, gastric cancer, colorectal cancer, and pancreatic cancer, the amplification of CDK4 and cyclin D1 is often seen. These results imply that CDK4 might be a useful target for therapy intervention and a significant biomarker for tumor development.

Figure 1 describes the signaling pathways of CDK4 and CDK6 in cancer cells and their functions. Figure 1 CDK4 and CDK6 signaling pathways in cancer cells. (Goel S, et al., 2022)

CDK4 is expressed in normal esophageal tissues in low quantities. In esophageal squamous cell carcinoma, however, CDK4 expression is much increased. Tumor development, invasion, and metastases are linked to this overexpression. Indicating its possible use as a prognostic marker for ESCC, high CDK4 expression corresponds with advanced tumor stages and poor differentiation.

Gastric cancer tissues have far greater CDK4 expression than both normal gastric tissue and chronic gastritis. Though it is not much correlated with tumor penetration depth, the overexpression of CDK4 is connected to the early molecular processes in gastric cancer formation. For gastric cancer, CDK4 has shown promise as a diagnostic and prognostic marker.

In colorectal cancer, CDK4 expression is raised in adenomas as well as cancer tissues; this is correlated with tumor development. Tumor differentiation, lymph node metastases, and Duke's clinical stage all have been linked to the overexpression of CDK4 in colorectal cancer. A shorter survival time is linked to higher cytoplasmic expression of CDK4, so CDK4 is a crucial prognostic factor.

It has been shown that the genesis and course of pancreatic cancer is intimately correlated with CDK4 overexpression. With overexpression more prevalent in poorly differentiated tumors and those with lymph node metastases, studies have shown greater degrees of CDK4 expression in pancreatic cancer tissues than in chronic pancreatitis. This implies that in pancreatic cancer CDK4 might be a useful target for early detection, prognosis, and therapeutic intervention.

Therapeutic Implications of CDK4 Inhibition

Given its essential function in the control of cell cycle progression and its involvement in cancer, CDK4 has become a target of great promise for cancer treatment. Palbociclib is one of the most well-known CDK4 inhibitors; by blocking CDK4 and CDK6, it has been shown to reasonably delay the development of advanced breast cancer. Particularly in tumors with mutations in genes like PIK3CA, palbociclib has shown effectiveness in concert with other medicines. Targeting CDK4 helps this treatment method try to stop the unchecked cell proliferation causing cancer development.

Apart from palbociclib, additional CDK4 inhibitors under investigation in clinical trials aim to sensitize tumors to various treatment modalities, including chemotherapy and targeted treatments. Because they provide a possibility for precision medicine, wherein medication may be customized to individuals with unique mutations or overexpressed proteins, CDK4 inhibitors are very appealing.

References:

Goel S, Bergholz JS, Zhao JJ. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022 Jun;22(6):356-372.
Fassl A, Geng Y, Sicinski P. CDK4 and CDK6 kinases: From basic science to cancer therapy. Science. 2022 Jan 14;375(6577):eabc1495.

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