R01AI187203

Host cell reprogramming by human papillomavirus E7 proteins - Project summary/abstract

Human papillomavirus (HPV)-encoded proteins engage cellular proteins to potently reprogram host cell signaling pathways, in doing so establishing a cellular environment conducive to viral replication and persistence.

The HPV E6 and E7 proteins provide much of the viral reprogramming activity and, in the case of ‘high-risk’ HPV E6 and E7, so significantly disrupt cell signaling that they promote cellular transformation.

Intensive research efforts have identified many host cell binding partners of HPV E7, some that interact with HPV E7 proteins from most virus genotypes and others that interact with only a subset of the HPV E7s.

However, there is a major open question regarding how many of the host cell targets of high-risk and low-risk HPV E7 proteins are required to reprogram host cell signaling and, for high-risk HPV E7, to drive cellular transformation.

We propose that the RB1 and PTPN14 tumor suppressors are two essential E7 targets and their inactivation dominates the biological activity of E7.

RB1 is a well-known target of many HPV E7 proteins that must be inactivated for high-risk HPV to cause cellular transformation.

High-risk HPV E7 proteins can degrade RB1, which is not a property of low-risk HPV E7s.

It is not known how RB1 degradation, in addition to binding, enables high-risk HPV E7 to alter cell signaling or to promote cellular transformation.

Moreover, RB1 inactivation is necessary but insufficient for the transforming activity of high-risk HPV E7.

We discovered that a second target of many HPV E7 proteins is PTPN14.

Our published and preliminary data show that HPV E7 proteins degrade PTPN14 and that PTPN14 degradation activates YAP1 signaling.

We also found that high-risk HPV E7 must degrade PTPN14 and activate YAP1 to immortalize primary human keratinocytes.

Our hypothesis is that RB1 degradation and PTPN14 degradation are independent activities of high-risk HPV E7 proteins that cooperate to reprogram the host cell and drive cell transformation.

The aims are 1) to determine how degradation of RB1 and PTPN14 contribute to host cell reprogramming and 2) to determine how degradation of PTPN14 and RB1 contribute to HPV E7 transforming activity.

Our research will determine how HPV E7 reprograms host cell signaling and how inhibiting essential activities of HPV E7 could limit cell growth.

By testing whether a subset of the many proposed targets of HPV E7 underlie most of its biological activity, we will advance the understanding of viral oncoprotein activity, updating the model to reflect the established concept that altering a small number of host targets is sufficient for cellular transformation.

Trustees Of Tufts College

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Massachusetts United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have decreased 13% from $3,381,578 to $2,938,414.