The retinoblastoma gene, known as RB1, provides instructions for creating a protein called pRB. This gene is important for maintaining cellular health and controlling cell growth and division within the body.
The RB1 Gene’s Role in Healthy Cells
The pRB protein functions as a tumor suppressor, helping regulate cell growth and preventing cells from dividing too rapidly. In its active state, pRB acts like a “brake” on cell division, specifically by restricting the cell’s ability to replicate its DNA.
The pRB protein achieves this by binding to and inhibiting E2F transcription factors. These factors promote gene expression necessary for a cell to progress through its cycle, particularly from the G1 (first gap) phase to the S (synthesis) phase, where DNA replication occurs. By keeping E2F-DP inactivated, pRB maintains the cell in the G1 phase, preventing progression through the cell cycle.
When a cell is ready to divide, pRB is inactivated through phosphorylation, which allows the cell cycle to progress. This precise regulation ensures that cells only divide when appropriate, preventing the unchecked proliferation that characterizes cancerous growth. Beyond cell cycle control, pRB also interacts with other proteins to influence cell survival, programmed cell death (apoptosis), and cell differentiation.
The pRB protein also recruits chromatin remodeling enzymes, such as methylases and acetylases, which influence how DNA is packaged and accessed. This allows pRB to integrate signals from various pathways and translate them into specific changes in protein complexes on the DNA. Through these actions, RB1 plays a role in gene transcription, DNA replication, DNA repair, and mitosis, all important processes for normal development and the prevention of cancer.
How RB1 Gene Mutations Lead to Retinoblastoma
Mutations in the RB1 gene are directly linked to the development of retinoblastoma, a rare type of eye cancer that primarily affects young children. This cancer arises when both functional copies of the RB1 gene are inactivated within a retinal cell. This mechanism is explained by Knudson’s “two-hit hypothesis,” which states that two distinct genetic “hits” or mutations are necessary for a tumor suppressor gene, like RB1, to lose its function and lead to cancer.
In hereditary retinoblastoma, a child inherits one mutated copy of the RB1 gene from a parent. This “first hit” is present in all cells of their body, predisposing them to the disease. A “second hit,” a new somatic mutation or loss of the remaining healthy RB1 copy, then occurs in a retinal cell, leading to tumor development. Because the first mutation is already present in every cell, individuals with hereditary retinoblastoma often develop multiple tumors, which can appear in both eyes (bilateral retinoblastoma). The average age of diagnosis for bilateral cases is around 12 months.
In sporadic (non-hereditary) retinoblastoma, individuals are born with two normal copies of the RB1 gene. In this form, both “hits” are somatic mutations, meaning they occur randomly and independently in the same retinal cell during early childhood. The low probability of two such independent mutations occurring in a single cell explains why sporadic retinoblastoma results in a single tumor in one eye (unilateral retinoblastoma) and presents at a later age, with a mean diagnosis around 24 months.
When both copies of the RB1 gene are inactivated, the pRB protein is no longer functional. This loss of functional pRB means the “brake” on cell division is removed, allowing retinal cells to grow and divide uncontrollably. This unchecked proliferation leads to the formation of cancerous tumors in the retina. While the two-hit hypothesis provides a basic understanding, additional genetic changes can also influence the development and growth of retinoblastoma tumors.
The Broader Impact: RB1 and Other Cancers
While the RB1 gene is most recognized for its role in retinoblastoma, its dysfunction extends beyond this specific eye cancer, contributing to the development and progression of various other malignancies. The RB1 pathway is important to many cellular processes, and its disruption can have widespread consequences throughout the body.
Loss of RB1 function is observed in a range of adult cancers. For instance, RB1 inactivation is detected in a high percentage of sporadic small cell lung cancers (SCLC), with estimates reaching close to 90%. This suggests a direct contribution to the initiation of these aggressive lung tumors, and germline RB1 mutations can also predispose individuals to SCLC.
The RB1 gene also plays a part in the development of osteosarcoma, a type of bone cancer. RB1 inactivation occurs in approximately 20-40% of osteosarcoma cases, and its loss contributes to tumor progression, often linked with unfavorable patient outcomes. Changes in the RB1 gene have also been identified in some breast cancer cases, where RB1 inactivation can enhance stem cell-like behaviors and promote malignant progression.
Beyond these, somatic RB1 mutations have been reported in other cancers, including melanoma and certain leukemias. Individuals with hereditary retinoblastoma, who carry a germline RB1 mutation in all their cells, have an increased risk of developing secondary cancers outside the eye later in life, such as pineal gland tumors (pinealoma), soft tissue sarcomas, and melanoma. The involvement of RB1 demonstrates its general role as a tumor suppressor, extending its influence far beyond its namesake cancer.