Chapter 34: Cell Proliferation

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34.4:

Positive Regulator Molecules

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Cell Biology

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JoVE Core Cell Biology

Positive Regulator Molecules

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34.3: The Cell Cycle Control System

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34.5: Inhibition of CDK Activity

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The positive regulator molecules promote the transition through various stages of the cell cycle via the interaction of two protein groups: cyclins and cyclin-dependent kinases or Cdks. Mammalian cells contain around nine Cdks, with four of them, Cdk1, Cdk6, Cdk4, and Cdk2, involved in the cell cycle. The activity and specificity of any given Cdk depends on the binding of cyclins. Cyclins are grouped as G1, G1/S, S, or M phase cyclins, and their expression is specific to the stage they trigger For instance, in the G1 phase, cyclin D binds to Cdk4 and Cdk6, promoting the cell to the late G1 phase. Next, cyclin E accumulates and forms a complex with Cdk2. The cyclin E-Cdk2 complex, along with the cyclin D-Cdk4/6, triggers the G1 to S transition, which irreversibly commits the cells into the cycle. At the start of S phase, cyclin-E remains elevated and bound to Cdk2. In addition, cyclin-A level rises and combines with Cdk2. Both the complexes are directly responsible for DNA replication. Although cyclin E levels fall, cyclin-A levels are high throughout the S and G2-phases. At the G2-M transition, cyclin A levels drop and cyclin B levels rise. Cyclin B combines with Cdk1, triggering the start of mitosis. The levels of mitotic cyclins fall mid-mitosis, thus inactivating the Cdk. The inactive Cdk has a protein loop that blocks substrate protein access to the active site. It is only when a specific cyclin binds to the Cdk, that the loop moves away from the active site, thus partially activating Cdk. The complete activation of the Cdk-cyclin complex depends on another enzyme called Cdk activating kinase or CAK. The CAK phosphorylates an amino acid near the active site causing a conformational change in Cdk, enabling the Cdk-cyclin complex to phosphorylate its target proteins and induce specific cell cycle stage events.

34.4:

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.

Proteins, such as cyclin and cyclin-dependent kinases, are positive regulator molecules responsible for the cell cycle’s progression through various checkpoints. The cyclins were initially named such because their synthesis and degradation assume a cyclical pattern. There are at least four functional cyclins whose concentration fluctuates predictably across the cell cycle. When a cell gets promoted to the next stage, the cyclins of the previous phase get degraded. It is the changes in the cyclin concentration that trigger various cell cycle events.

Cyclins form an active complex with protein kinases that can phosphorylate specific target proteins during the cell cycle. Because these kinases need cyclin for activation, they are called cyclin-dependent kinases or Cdks. In the absence of cyclin, the Cdks are inactive, and in the absence of a fully activated cyclin/Cdk complex, the cell fails to pass through the checkpoints.

The positive regulator molecules are expressed by genes that belong to a group called proto-oncogenes. When mutated, these become oncogenes that cause the cell to become cancerous. For instance, a mutation that causes the Cdks to become active even in the absence of cyclin can cause the mutant cell to pass uninterrupted through the checkpoints leading to uncontrolled growth and proliferation.

Suggested Reading

Deshpande, Amit, Peter Sicinski, and Philip W. Hinds. "Cyclins and cdks in development and cancer: a perspective." Oncogene 24, no. 17 (2005): 2909.
Johnson, D. G., and C. L. Walker. "Cyclins and cell cycle checkpoints." Annual review of pharmacology and toxicology 39 (1999).

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