Question

A genetic variant of the retinoblastoma protein, called PSM-RB (phosphorylation site mutated \(\mathrm{RB}\) ), is not able to be phosphorylated by the action of CDK4/cyclin D1 complex. Explain why PSM-RB is said to have a constitutive growth-suppressing action on the cell cycle.

Short answer

Answer: PSM-RB (phosphorylation site mutated RB) exhibits a constitutive growth-suppressing action on the cell cycle because it cannot be phosphorylated by the CDK4/cyclin D1 complex due to mutations in its phosphorylation sites. As a result, PSM-RB remains unphosphorylated and in its active form throughout the cell cycle, continuously binding to E2F transcription factors and preventing the transcription of genes required for progression from the G1 phase to the S phase. This perpetual suppression of cell cycle progression by PSM-RB is what gives it its constitutive growth-suppressing action.

Step-by-step solution

Understand the retinoblastoma protein's role in the cell cycle

The retinoblastoma protein (RB) plays a crucial role in regulating the cell cycle by controlling the progression from the G1 phase to the S phase. During the G1 phase, RB binds to E2F transcription factors, effectively inhibiting them. E2F proteins are required for the expression of genes that drive the cell to progress into the S phase. When RB is bound to E2F proteins, it prevents these genes from being transcribed, thereby inhibiting the cell cycle progression.

Investigate the significance of RB phosphorylation in the cell cycle

Phosphorylation of RB by cyclin-dependent kinases (CDKs) partnered with cyclins, especially CDK4/cyclin D1 complex, leads to its inactivation. When RB is phosphorylated, it can no longer bind E2F proteins, and these transcription factors are free to activate the expression of genes that drive the cell into the S phase. Therefore, the phosphorylation of RB is necessary for the progression of the cell cycle.

Explain the unique feature of PSM-RB

The genetic variant PSM-RB (phosphorylation site mutated RB) is unable to be phosphorylated by the CDK4/cyclin D1 complex. This inability is due to mutations in the phosphorylation sites of RB, which are the target sites for CDK4/cyclin D1. As a result, PSM-RB remains unphosphorylated throughout the cell cycle.

Describe the constitutive growth-suppressing action of PSM-RB

Since the genetic variant PSM-RB cannot be phosphorylated by the CDK4/cyclin D1 complex, it remains in its active form throughout the cell cycle. Consequently, it continually binds to E2F transcription factors, preventing the transcription of genes necessary for the progression from the G1 phase to the S phase. This perpetual suppression of cell cycle progression by PSM-RB is referred to as having a constitutive growth-suppressing action on the cell cycle.

Key concepts

Retinoblastoma Protein

The retinoblastoma protein (often abbreviated as RB) is a critical regulator of the cell cycle, particularly at the transition from the G1 phase to the S phase. In its active form, RB binds to E2F transcription factors, which are essential for initiating the transcription of genes that push the cell into the DNA synthesis phase, or S phase. By attaching itself to E2F, the retinoblastoma protein effectively inhibits the transcription of these genes, thereby halting cell cycle progression at the G1 stage. This prevents cells from prematurely entering the S phase and ensures that the cell only progresses when conditions are optimal.
We can think of RB as a guardian that keeps the cell cycle on hold until everything is ready for the next stage of growth. Without this control, cells might divide uncontrollably, leading to growth-related issues.

CDK4/cyclin D1 Complex

The CDK4/cyclin D1 complex represents a crucial checkpoint in the regulation of the cell cycle. Cyclin-dependent kinase 4 (CDK4) teams up with cyclin D1 to form a complex that plays a pivotal role in the transition from the G1 to the S phase. This complex achieves its regulatory function by phosphorylating the retinoblastoma protein.
- When CDK4/cyclin D1 phosphorylates RB, it undergoes a structural change. - This change releases the E2F transcription factors, enabling them to activate genes necessary for entering the S phase.
These genes are essential for DNA replication, a critical step before a cell divides. Thus, the CDK4/cyclin D1 complex is fundamental in moving the cell cycle forward and allowing controlled cell growth.

E2F Transcription Factors

E2F transcription factors are the gatekeepers of the genetic instructions needed for the cell cycle's transition from the G1 phase into the S phase. They promote the expression of genes required for DNA replication and related processes.
Under normal circumstances, when RB is not phosphorylated, it binds to E2F transcription factors, thereby inhibiting their function and stalling cell cycle progression. Upon phosphorylation by the CDK4/cyclin D1 complex, these E2F transcription factors are liberated from RB and can start the transcription of crucial cell cycle genes.
This liberation allows the cell to move past the G1 checkpoint and enter the DNA synthesis phase. Hence, E2F transcription factors are key players that help to precisely time the advancement of the cell cycle, ensuring that DNA replication and cell division occur at the right moment.