Molecular studies on papillomavirus infection that may have significant ramifications for diagnosing and treating HPV preneoplastic lesions and cervical cancer

The studies on papillomavirus that are being carried out in Dr. Howley’s lab have enormous potential for impacting current diagnosis and treatment of HPV associated preneoplastic lesions and cancers. The lab has honed in on specific molecular pathways and biochemical reactions that may be essential for the oncogenic activity of HPV, laying the groundwork for future efforts at developing novel therapies to treat precancers or to arrest cervical cancer growth. There is also a need for improved biomarkers that indicate the presence of either HPV infection or pre-neoplastic lesions that may develop into full-blown cervical cancer, since the current diagnostic test for precancerous cervical cancer lesions, the cytologic Papanicolaou (PAP) smear, is prone to false negatives.

Each year in the US there are over 10,000 new cases of cervical cancer and over 3000 deaths attributed to this disease. Worldwide, cervical cancer is the third most common cause of death due to cancer, responsible for 300,000 deaths each year. HPV is also linked to other anogenital cancers and some upper airway cancers.  Dr. Howley’s medically-relevant research represents a unique opportunity for life science companies to support the development of new therapeutics and diagnostics for cervical cancer.

Dr. Howley’s lab is extending its important studies on papillomavirus biology, with the objective of gaining insights that may eventually lead to a clinical benefit. Elucidation of the complete spectrum of oncogenic activities for the E6 and E7 proteins remains an important task. His laboratory identified the cellular E6 associated protein (E6AP) as the ubiquitin ligase that acts in concert with the HPV-encoded E6 to promote p53 breakdown via ubiquitylation and subsequent proteasomal destruction, but the cellular genes that regulate this biochemical process remain elusive. The lab is studying basic molecular aspects of the ubiquitin-proteasome protein degradation pathway.  Dr. Howley’s lab is employing advanced molecular and chemical screening techniques to probe the molecular signaling involving the HPV-encoded E2 protein, which is a key regulator of viral transcription, viral genome replication and viral persistence.

Dr. Howley’s lab is using RNA interference and chemical genetic technologies to identify the cellular proteins as well as chemical inhibitors that affect the ability of HPV E6 protein to block p53 tumor suppression and genomic “guardian” activities by signaling the cellular machinery to degrade p53.
 

Dr. Howley’s laboratory has investigated aspects of papillomavirus biology, with a particular emphasis on the specific roles of the papillomavirus-encoded E6 and E7 oncoproteins as well as the E2 regulatory protein. Papillomavirus is an intriguing cancer model, since sexually transmitted infection of particular subtypes of human papillomavirus (HPV) can lead to the development of cervical cancer. The HPV-encoded E6 polypeptide is particularly interesting because of its ability to facilitate the catabolism of the key tumor suppressor/surveillance protein p53. This is a consequence of the enhanced ubiquitylation and subsequent proteasomal degradation of p53 that E6 fosters. Moreover, E6 has other functions, mediated via protein-protein interactions. In a recent study, the lab has demonstrated that both E6 and E7 are capable individually of conferring “resistance” to a particular form of apoptosis called anoikis, demonstrating a key property of these oncoproteins. However, their data support the contention that this anoikis-inhibiting property does not fully account for the oncogenic activities of these proteins.

In other studies, the lab has delved into the function of the papillomavirus E2 regulatory protein, which is involved in a myriad of metabolic events. The lab established that the bromodomain protein Brd4 associates with E2 as well as modulates E2-specific transcriptional activation properties. In a recently completed whole genome siRNA screen, his lab has identified three distinct molecular pathways used by E2 to regulate the expression of the viral E6 and E7 oncoproteins.
 

Biological Mechanisms and Pathways

• Apoptosis •
• Infectious disease •
• Oncology •
• p53 •
• Ubiquitin •
• Ubiquitin
•  

Cancer

• Apoptosis •
• Cancer •
• Cervical cancer •
• Oncology •
• p53
•  

Disease Mechanisms

• Cancer •
• Cervical cancer •
• HPV •
• Infectious disease
•  

Infectious Disease

• HPV •
• Papillomavirus
•  

Research Tools and Instrumentation

• Biomarker •
• RNA interference •
• siRNA screen
•  

Therapeutic Discovery Tools and Assays

• Biomarker •
• Cancer
•  

Therapeutics

• PAP smear
•