Question

Human papillomavirus (HPV) is a causative factor in over \(95 \%\) of cervical cancers. Other viruses such as Epstein-Barr, Kaposi's sarcoma-associated herpes virus, and hepatitis B virus also are known to cause cancer. For this to happen, viral genes that promote entry into Sphase or that promote resistance to apoptosis must become incorporated into the host cell DNA in a host cell that also survives the viral infection. If the viral gene within the host DNA is then overexpressed in an unregulated manner, it is a viral oncogene. The Epstein-Barr protein binds to the cellular Rb-binding pocket and displaces E2F from Rb. The effect would be to A. require that \(R b\) be phosphorylated. B. stall the cell cycle in the G_phase. C. increase the transcription of gene products for S-phase proteins. D. inhibit the action of cyclin-dependent kinases (Cdks). E. inhibit apoptosis.

Short answer

Answer: The Epstein-Barr protein binding to the cellular Rb-binding pocket increases the transcription of gene products for S-phase proteins, promoting entry into the S-phase.

Step-by-step solution

Understanding the role of Epstein-Barr protein in the cell cycle

The Epstein-Barr protein binds to the cellular Rb-binding pocket and displaces E2F from Rb. This means that the E2F protein, which has a role in activating genes involved in S-phase entry, is no longer bound to Rb.

Analyzing the choices

Let's go through each choice and see if it is a logical consequence of the Epstein-Barr protein binding to the Rb-binding pocket. A. Require that Rb be phosphorylated: Phosphorylation of Rb would cause the release of E2F, but since E2F is already released due to the presence of the Epstein-Barr protein, this choice is not correct. B. Stall the cell cycle in the G1 phase: Epstein-Barr protein causes E2F to be released, which would promote entry into the S phase. Therefore, this choice is not correct. C. Increase the transcription of gene products for S-phase proteins: This choice makes sense because the release of E2F would lead to an increase in genes promoting entry into the S phase. D. Inhibit the action of cyclin-dependent kinases (Cdks): Since Epstein-Barr protein affects Rb and E2F, it does not directly inhibit the action of Cdks. This choice is not correct. E. Inhibit apoptosis: Although the question mentions the role of viral genes in promoting resistance to apoptosis, it does not specifically link the release of E2F to this outcome. This choice is not the most directly related to the given information.

Choose the correct answer

Based on our analysis, the correct answer is C. By binding to the cellular Rb-binding pocket and displacing E2F from Rb, the Epstein-Barr protein would increase the transcription of gene products for S-phase proteins, promoting entry into the S-phase.

Key concepts

Human Papillomavirus (HPV)

Human papillomavirus (HPV) is a common virus with over 100 different types, some of which are linked to various cancers, most notably cervical cancer. HPVs infect epithelial cells, often in the genital or oral areas, and can lead to benign lesions like warts or malignant transformations in host cells.

In the context of cervical cancer, high-risk HPV types (especially HPV-16 and HPV-18) integrate their DNA into the host cell genome, potentially leading to the overexpression of viral oncogenes. These oncogenes can interfere with normal cell cycle regulation and promote resistance to apoptosis, facilitating uncontrolled cell division and tumor development.

Cervical Cancer

Cervical cancer arises from the cervix and is closely linked with HPV infection, particularly persistent infections with high-risk HPV types. The transformation from a benign infection to a malignant tumor involves multiple steps, including the integration of HPV DNA into the host genome, the overexpression of viral proteins (E6 and E7), and the disruption of tumor suppressor functions like those performed by Rb protein and p53.

This interference with tumor suppressor mechanisms leads to the loss of control over the cell cycle and evasion of apoptosis, two cellular hallmarks of cancer development.

Epstein-Barr Virus

The Epstein-Barr virus (EBV) is a member of the herpesvirus family and is best known for causing infectious mononucleosis ('mono'). However, EBV infection is also associated with various lymphoid and epithelial cancers, such as Burkitt lymphoma and nasopharyngeal carcinoma.

EBV contributes to oncogenesis by expressing viral proteins that interfere with cell cycle regulation and apoptosis, like the protein that binds to Rb, which displaces the E2F transcription factor and leads to the deregulation of the cell cycle progression.

Apoptosis

Apoptosis is the process of programmed cell death that removes damaged or unwanted cells in an organized manner. This process is critical for maintaining tissue homeostasis and preventing the development of cancer.

Viruses like HPV and EBV can alter apoptosis pathways to promote cell survival, thereby allowing the infected cells harboring viral oncogenes to evade the immune system and accumulate additional genetic damage, which can contribute to the transformation into cancer cells.

Cell Cycle

The cell cycle is an ordered set of events leading to cell division and the replication of its DNA to produce two daughter cells. The cycle is divided into four main phases: G1, S (DNA synthesis), G2, and M (mitosis).

Regulatory checkpoints at different phases ensure DNA integrity and proper cell growth. Viral oncogenes can disrupt the control over these checkpoints, especially the G1/S transition, forcing the cell into DNA replication despite potential errors or damage, which is a critical step in oncogenesis.

Rb Protein

The Rb protein, or retinoblastoma protein, is a key regulator of the cell cycle transition from G1 to S phase. It acts as a tumor suppressor by inhibiting the activity of E2F transcription factors, which are necessary for the progression of the cell cycle into the S-phase. When Rb is inactivated, such as through phosphorylation or by binding of viral proteins (e.g., from HPV or EBV), E2F is released and activates the transcription of genes that are required for DNA synthesis and other S-phase functions.

E2F Transcription Factor

E2F transcription factors are crucial for controlling the expression of genes involved in DNA replication, repair, and cell cycle progression. When bound by Rb protein, their activity is inhibited, preventing premature S-phase entry.

Viral oncogenes can disrupt this regulation by inactivating Rb, freeing E2F to stimulate the transcription of S-phase genes. This action by viruses like EBV, which binds and inactivates Rb, underscores their role in promoting cell cycle progression and potentially leading to oncogenic transformation.

S-phase Entry

Entry into the S-phase of the cell cycle is a critical point of regulation. This phase is where DNA replication occurs, and it needs to be tightly controlled to prevent genomic instability. The G1/S checkpoint ensures that all conditions are favorable for DNA synthesis, and it involves several proteins, including Rb and E2F.

Viruses can influence this checkpoint by manipulating Rb's ability to restrain E2F activity, thus causing the unregulated transcription of S-phase genes and promoting S-phase entry, which can lead to genomic instability and an increased risk of cancerous transformation.