Professor Bramanandam Manavathi, faculty in the Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH) and his team has been working on ‘HPIP-a new culprit gene in the development of cancer”. Their research findings have been recently published under title “Hematopoietic PBX-interacting protein is a substrate and an inhibitor of the APC/C-Cdc20 complex and regulates mitosis by stabilizing cyclin B1” in J Biol Chem. 2019 Jun 28;294(26):10236-10252.
Brief up of the findings:
Our human body has several trillion cells. Each and every cell undergoes cell division, duplication of cells, to maintain our body system. In normal cells, cell division proceeds through a series of precisely timed and carefully regulated stages of growth (G1 phase), DNA synthesis (S phase), preparatory phase for division (G2) chromosome segregation (M-mitosis) and division (cytokinesis) that produce two identical daughter cells. There are ‘checkpoints ‘at the transition of each phase to verify and examine abnormality like DNA damage, proper chromosome distribution (chromosome segregation) in order to decide/determine whether or not the cell has to move forward for cell division. These roles are monitored by sets of proteins like CyclinA, Cyclin B1, Cyclin E etc. and they act at different time and phases.
Our body has a well-regulated mechanism to control the cell division. Uncontrollable cell division leads to cancer. How cell division goes awry? Studying the defect or role of proteins in each phase of cell cycle is an exploring area in the field of cancer to control cancer cell growth. Our main study focuses on the M phase, where chromosome separation and distribution to pre-daughter cell occur, and cytokinesis, where cell division takes place to give raise two daughter cells.
The G2/M phase transition of cell cycle is controlled by a protein called cyclin B1. Once cyclin B1 is degraded by another protein complex, APC/C, the cell starts entering M phase from G2 phase. In the transition of this phase, cyclin B1 degradation has to be prevented from APC/C to promote proper G2 to M phase transition. We discovered that HPIP protein protect the cyclin B1 in this transient period making itself sacrifice or degraded (sacrificing itself for Cyclin B1) to APC/C-CDC20 machinery to ensure the cyclin B1 function for timely entry of the cell to M phase.
The duplicated chromosomes which are derived from the S phase to be distributed to the daughter cells during M phase. The chromosomes are held and monitored by a checkpoint protein called as spindle assembly checkpoint (SAC) protein complex and give license to the cells to segregate the chromosome to daughter cell following cytokinesis. By lowering the HPIP production using the viral transduction method, we discovered that there is a chromosome segregation defect with multiple spindle formation and chromosomal abnormalities resulting in a defective cytokinesis and delay in M phase transition. This study not only underscores the importance of HPIP gene in cell division, but also signifies how HPIP overexpression observed in various cancers including breast cancer which is highly prevalent in India, is responsible for tumor growth. It implies considering HPIP as a potential therapeutic target in cancer therapy. This work is published in the prestigious Journal of Biological Chemistry (JBC).
Earlier our group has first reported the role of HPIP gene in breast cancer (Bugide et al., Oncogene 2015). Later other research groups around the world have expanded its significance in other cancers such as liver, brain, stomach etc. While HPIP role in cancer is well established to consider as a potential novel therapeutic target in cancer, its protein structure to be unveiled that might motivate us to identify the inhibitors for HPIP. We are partially successful in that direction as we found that it is a dimeric protein and its dimerisation is important for its functions (unpublished data). So we are in the process of identifying the small molecular synthetic inhibitors to block its dimerisation, its oncogenic functions and thus cure cancer.
Title of the paper:
Hematopoietic PBX-interacting protein is a substrate and an inhibitor of the APC/C–CDC20 complex and regulates mitosis by stabilizing cyclin B1
Research team participated in this work:
Saratchandra Singh Khumukcham, Venkata Subrahmanyam Kumar Samanthapudi, Vasudevarao Penugurti, Anita Kumari, P.S. Kesavan, Loka Reddy Velatooru, Siva Reddy Kotla, Aprotim Mazumder and Bramanandam Manavathi.
Professor Bramanandam Manavathi, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad- 500046, India
Other research team participated in this work:
Dr Aprotim Mazumder from, TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research Hyderabad, Hyderabad – 500107, Telangana, India, also participated in this research work.
Department of Biotechnology (DBT), India is financially supported this work.
Khumukcham SS, Samanthapudi VSK, Penugurti V, Kumari A, Kesavan PS, Velatooru LR, Kotla SR, Mazumder A, Manavathi B.Hematopoietic PBX-interacting protein is a substrate and an inhibitor of the APC/C-Cdc20 complex and regulates mitosis by stabilizing cyclin B1.
J Biol Chem. 2019 Jun 28;294(26):10236-10252.