The retinoblastoma gene (\(RB1\)) is the prototypical tumor suppressor gene, classifying it among the most significant regulators of cell growth and division. The protein it produces, pRB, acts as a master brake on the cell cycle, ensuring a cell only divides when conditions are correct. The discovery of this gene and its function reshaped the understanding of how cancer develops at a molecular level.
Defining Tumor Suppressor Genes
Tumor suppressor genes (TSGs) are normal genes that encode proteins designed to control cell division and prevent the uncontrolled proliferation characteristic of cancer. These genes function like the brakes in a car, actively working to slow down or halt the cell cycle, repair damaged DNA, or initiate programmed cell death (apoptosis). Unlike oncogenes, which promote cancer, TSGs must be inactivated to allow tumor growth.
The concept that both copies of a tumor suppressor gene must fail to cause cancer is formalized in the “two-hit hypothesis,” originally proposed by Alfred Knudson for retinoblastoma. Every cell contains two alleles of the \(RB1\) gene. The loss of function in just one copy is typically compensated for by the remaining functional copy. Cancer develops only when both alleles are mutated or inactivated, leading to a complete loss of protective function.
In hereditary cancer, an individual inherits one defective allele, representing the first “hit” in every cell. Only one additional, spontaneous mutation (the second “hit”) is then required in a susceptible cell to trigger tumor growth. In non-hereditary, or sporadic, cases, both mutations must occur independently in the same somatic cell, which explains why these cancers usually arise later in life.
The RB Protein’s Role in Cell Cycle Control
The retinoblastoma protein (pRB) acts as a precise gatekeeper for the cell division process, controlling the transition from the G1 phase to the S phase of the cell cycle. The decision to move from G1 to S is an irreversible commitment to divide, making this checkpoint a critical regulatory point.
When the cell is not ready to divide, pRB is in an under-phosphorylated, or “active,” state. In this state, it physically binds to and represses the E2F family of transcription factors. E2F factors are responsible for turning on the genes necessary for DNA replication and entry into the S phase. By binding to E2F, pRB locks down the genetic program for cell division, preventing the expression of S-phase-promoting genes.
To move past the G1 checkpoint, the cell must receive growth signals that activate specific enzymes called cyclin-dependent kinases (CDKs). CDKs add phosphate groups to pRB, a process called phosphorylation. As pRB becomes progressively more phosphorylated, its shape changes, causing it to release the E2F transcription factors.
The freed E2F proteins move to the nucleus and activate the transcription of genes required for DNA synthesis, allowing the cell to enter the S phase. This phosphorylation-mediated release is the molecular switch that controls the cell cycle, ensuring proliferation occurs only in response to proper external signals.
Consequences of \(RB1\) Failure in Cancer
The failure of the \(RB1\) tumor suppressor gene directly leads to the uncontrolled cell proliferation characteristic of cancer. When both copies of the \(RB1\) gene are mutated or deleted, the cell cannot produce functional pRB protein. Without a functioning pRB gatekeeper, the E2F transcription factors are permanently active, constantly signaling the cell to replicate its DNA and divide.
This permanent bypass of the G1/S checkpoint means the cell loses its ability to pause and repair accumulated genetic damage. The most direct consequence of \(RB1\) inactivation is retinoblastoma, a malignant tumor of the retina that typically affects young children.
Inactivation of the \(RB1\) pathway is one of the most common alterations across human malignancies. Loss of \(RB1\) function is frequently observed in aggressive cancers, including small cell lung cancer, bladder cancer, and osteosarcomas. In these cancers, the functional loss of pRB contributes to the malignant phenotype, often combined with other genetic mutations.
The loss of pRB drives proliferation and contributes to genomic instability, accelerating the accumulation of other cancer-promoting mutations. \(RB1\) failure provides a potent selective advantage, allowing cancer cells to ignore normal growth-inhibitory signals and progress rapidly through the cell cycle.