Question

Mutations in the Rb gene are often associated with cancer. Draw or describe the mechanism/pathway by which a nonfunctional Rb protein can lead to cancer.

Answer 1

Rb gene is a tumor suppressor gene whose inactivation contribute to the development of tumor. Loss of function mutation of Rb gene is critical for the development of cancer with malignant phenotype by cell cycle deregulation. Rb gene is responsible to for retinoblastoma, it is a childhood tumor in retina. Rb gene is located in the chromosome 13q14.2. Tumor suppressor gene can suppress the development of cancer. Therefore, when these gene is mutated or functionally inactive, it leads to cancer.

Mechanism of Rb gene :- Rb gene encodes pRb(protein product), located in the nucleus (mass 110kDa). pRb is a phosphoprotein, so it can be inactive and active through phosphorylation and dephosphorylation respectively. pRb is a negative regulator of cell cycle. Normally, when the cells are in G0/G1 stage, pRb is active in its un or non-phosphorylated form. Active form of pRb binds E2F ( to make it inactive) before S phase. E2F is a transcription factor, by binding with it pRb represses it's gene transcription which is required for transition from G1 to S phase. Thus, non phosphorylated pRb stops the cell from entering into S phase. At the end of G1 stage, pRb is phosphorylated by cyclin D-CDK4, D-CDK6 and cyclin E-CDK2 and pRb become inactive and this phosphorylation reduces it's affinity for E2F. And E2F become heterodimerize by binding with DP factor(DNA binding proteins). Therefore, E2F able to transcribe and activates the S phase gene expression by which cell can enter into S phase.

When Rb gene is functionally inactive as well as non-functional by mutation, it is unable to bind E2F protein, therefore E2F transcription factors will always free to bind DP factor and they induces transcription of S-phase genes continuously. In this condition, cells are unable to halt the cell cycle process by checkpoints. In absence of checkpoints, cells divide uncontrollably, rate of cell proliferation increases which ultimately leads to cancer.

For better understanding, mechanism of Rb gene is given schematically in the following image.

Mutated Condition Rb] (uitated forom of Rb) Inactive F2F a unable to b DP bind with y sa Active Rb Sphase genes transcribe continuously and cell proliferates, division continously Normal Condition occur en Phosphomplation of Rb t. Phosphonglation of Rb release E2F Kb D-PDK 4160 EL E2F o nesponsive genes Unphosphorylated Rb bound to E2F transcription xaxxoodbox start of Nucleus Ph asphase genes