CDK-4 Human
Description
CDK4 partners with D-type cyclins (e.g., cyclin D1) to drive G1/S progression via:
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Rb phosphorylation: Releases E2F transcription factors to activate S-phase genes .
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Secondary targets: Direct phosphorylation of MYC, FOXM1, and Smad3 to modulate survival and senescence .
Two models describe CDK4 activity:
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Classic model: CDK4 fully phosphorylates Rb to inactivate it, enabling E2F release .
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Modern model: CDK4 initiates Rb mono-phosphorylation, creating isoforms that sequester E2F until CDK2 completes Rb inactivation .
Regulatory Mechanisms
Clinical Significance in Cancer
CDK4 dysregulation is oncogenic due to:
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Mutations: R24C in melanoma disrupts INK4 binding, causing constitutive activation .
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Amplification: Common in gliomas, sarcomas, and breast cancer .
Therapeutic CDK4/6 inhibitors (e.g., ribociclib, palbociclib) are FDA-approved for HR+/HER2− breast cancer:
Emerging Research Insights
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Hematopoiesis: CCND1-CDK4 accelerates G0/G1 transit in stem cells, enhancing engraftment without depleting progenitor pools .
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Resistance mechanisms: Prolonged CDK4/6 inhibitor exposure maintains T172 phosphorylation, enabling rebound signaling .
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Combination therapies: Synergy with PI3K inhibitors and immunotherapy is under investigation .
Future Directions
Product Specs
Product Science Overview
Cyclin-Dependent Kinase 4 (CDK4) is a crucial enzyme in humans, encoded by the CDK4 gene. It belongs to the cyclin-dependent kinase family, which plays a significant role in regulating the cell cycle. CDK4, in particular, is involved in the progression of the cell cycle from the G1 phase to the S phase, making it essential for cell division and proliferation .
CDK4 is a serine/threonine protein kinase that forms a complex with D-type cyclins (Cyclin D1, D2, and D3). This complex phosphorylates the retinoblastoma protein (Rb), leading to the release of the transcription factor E2F. The release of E2F allows the transcription of genes necessary for DNA synthesis and cell cycle progression .
The activity of CDK4 is tightly regulated by various mechanisms, including the binding of cyclin D and the inhibition by CDK inhibitors such as p16^INK4a. The balance between these regulatory factors ensures proper cell cycle control and prevents uncontrolled cell proliferation .
Mutations and dysregulation of CDK4 and its associated proteins have been linked to various cancers. For instance, a specific point mutation (R24C) in CDK4 has been identified in melanoma patients. This mutation disrupts the binding of CDK inhibitors, leading to unchecked CDK4 activity and promoting tumorigenesis .
Due to its critical role in cell cycle regulation, CDK4 has become a potential therapeutic target for cancer treatment. Several CDK4 inhibitors are currently being tested in clinical trials to evaluate their efficacy in treating different types of cancer .
Recombinant human CDK4 is produced using various expression systems, such as baculovirus-infected insect cells. This recombinant protein is used in research to study the biochemical properties and regulatory mechanisms of CDK4. It also serves as a valuable tool for screening potential CDK4 inhibitors for therapeutic applications .
