Human Papillomavirus (HPV) is a common infection. While most strains are harmless, a subset of “high-risk” types causes nearly all cases of cervical cancer, along with a significant portion of other anogenital and head and neck cancers. These oncogenic strains transform normal cells into malignant ones using two small viral proteins: E6 and E7. These proteins act as powerful oncogenes by hijacking the host cell’s regulatory machinery. Understanding how E6 and E7 function reveals the mechanism by which the virus drives the infected cell toward uncontrolled division and survival.
Viral Origin and Expression
The E6 and E7 proteins are encoded by the early (E) genes within the HPV genome, which is circular, double-stranded DNA. During a typical, transient infection, the viral DNA remains separate from the host chromosomes in a structure called an episome. In this state, the viral E2 protein acts as a transcriptional repressor, tightly controlling the expression of E6 and E7. Most high-risk HPV infections are cleared by the immune system within one to two years, never progressing beyond this controlled, episomal stage.
Progression to cancer requires the infection to become persistent, which involves a crucial genetic event. In most HPV-related cancers, the viral DNA integrates randomly into the host cell’s chromosome. This integration typically disrupts the E2 gene, eliminating the repressor protein that normally keeps E6 and E7 production in check. The resulting loss of the E2 brake leads to the sustained, high-level expression of E6 and E7 proteins, making them the central drivers of oncogenesis.
E6’s Mechanism: Targeting the p53 Tumor Suppressor
The E6 protein’s primary function is the targeted destruction of the cellular p53 protein, a tumor suppressor often called the “guardian of the genome.” In healthy cells, p53 senses DNA damage or cellular stress and initiates protective responses. These responses include halting the cell cycle for repair or triggering apoptosis (programmed cell death). Removing cells with damaged DNA prevents mutations from accumulating.
To neutralize this defense, E6 binds directly to E6AP, a cellular enzyme and ubiquitin ligase. This binding forms a complex that tags the p53 protein with ubiquitin molecules. This tag marks p53 for rapid destruction by the cell’s proteasome machinery. The degradation of p53 eliminates the cell’s main mechanism for responding to genetic instability, allowing the infected cell to ignore DNA damage and survive.
The concentration of p53 drops dramatically due to this E6-mediated degradation. This loss of the p53-dependent checkpoint allows genetic errors to accumulate. E6 also targets other cellular proteins for degradation, including those involved in cell polarity and adhesion, which further contributes to the malignant phenotype. However, the continuous destruction of p53 remains the foundational event that removes the safeguard against malignant transformation.
E7’s Mechanism: Inactivating the Rb Protein
The E7 protein works in concert with E6 by dismantling the second major tumor-suppressor pathway, governed by the Retinoblastoma (Rb) protein. Rb functions as a molecular gatekeeper at the G1-to-S phase transition of the cell cycle, ensuring the cell only commits to division when preparations are complete. Rb exerts control by binding tightly to and inactivating the E2F family of transcription factors, which are necessary for expressing genes required for DNA synthesis and cell division.
The E7 protein possesses a short amino acid sequence motif, known as the LXCXE motif, which allows it to bind directly to the active form of the Rb protein. Upon binding, E7 disrupts the Rb-E2F complex, causing the immediate release of the E2F transcription factors. Once free, E2F moves to the nucleus and activates the transcription of genes that drive the cell into the S phase, regardless of external signals.
E7 also promotes the degradation of Rb, further ensuring the cell cycle remains permanently deregulated. This perpetual activation mimics the state of an actively dividing cell, which the virus exploits to access the host cell’s DNA replication machinery. The combined actions of E6 and E7—removing the mechanism for cell death while forcing uncontrolled division—are necessary and sufficient to initiate cellular immortalization and cancer development.
Diagnostic and Therapeutic Significance
The sustained, high-level expression of E6 and E7 makes them indispensable biomarkers for identifying and tracking high-risk HPV infections progressing toward cancer. Unlike HPV DNA testing, which only confirms the presence of the virus, detecting the E6/E7 messenger RNA (mRNA) transcripts indicates active oncogene expression. This active expression is a strong indicator of persistent infection and a high likelihood of developing high-grade lesions.
The detection of E6/E7 mRNA is a valuable tool for risk stratification, helping clinicians determine which patients require immediate intervention versus those who can be monitored. The E7 protein’s action on Rb leads to a compensatory overexpression of the cellular protein p16. P16 is an indirect but highly specific marker of active oncogenesis, and immunohistochemical staining for p16 is routinely used to confirm high-grade HPV-related lesions.
Because E6 and E7 are continuously expressed and required for tumor survival, they represent near-ideal therapeutic targets. Emerging treatment strategies focus on neutralizing these viral proteins to restore the function of the host cell’s tumor suppressors. This includes developing therapeutic vaccines designed to stimulate the immune system’s T-cells to destroy E6 and E7-expressing cells. Advanced approaches involve gene therapy techniques, such as CRISPR/Cas9 or RNA interference, aimed at degrading the E6 and E7 mRNA transcripts, forcing cancer cells to undergo cell cycle arrest and apoptosis.