Hungy, Hungy....HPO!!!

   Delving deeper into the understandings and workings of the feeble, yet supremely interesting specimen, Drosophila grimshawi, I have finally decided on a gene that not only has unique implications affecting itself, but may one day help us to understand other larger queries, such as how to slow, or perhaps stop cancer. The hippo (Hpo) gene is crucial in more than just one specific way. It acts as a "slippery-slope" guardsman. Its main significant function, in tandem with sav & wts, is to regulate cell growth, reproduction, and programmed cell death (apoptosis). Coordination between these three processes needs to be balanced in order to maintain homeostasis in multicellular organisms. The reason I say hpo is a guardsman is because if hpo is mutated or missing, then cell growth and reproduction continues on, unchecked. That, along with no cell death, can cause the organs to become enlarged, and mutated, and ultimately lead to the death of the organism. If a cell becomes cancerous, and there is no cell death due to no hpo, then that cell will replicate and that can be disastrous. Not on hpo's watch! In 2003, the hippo gene made its debut in multiple publications simultaneously, becoming something of interest.

     This four allele, 2800bp gene is located between 15381k and 15385k. It has 2 exons and 669 amino acids. it belongs to the Ste20 family of kinases, consisting of over 20 members, including Ste20. This family trigger the activation of mitogen-activated protein kinases (MAPK) pathways in eukaryotes. Mammalian Ste20-family kinases, MST1 and MST2 are orthologs of hpo. Hpo contains three conserved domains: an amino-terminal kinase domain, a central autoregulatory domain that inhibits kinase activity, and a domain implicated in dimerization and binding Sav at its terminus.  Now that we have a better understanding its structure, lets continue on why Drosophila need it so badly. 

     The increase in cell number that comes with the growth of an organ or organism is a result from the fickle equilibrium between the three main components; cell proliferation, cell growth, and cell death during development. How these three processes are coordinated and executed with precision is not completely known. However we do know that without hpo, or its counter-parts (Sav & Wts), it will result in increased cell proliferation and reduced apoptosis. Studies believe and have suggested that these genes function in a common pathway, known as the Hpo pathway, that coordinately regulates cell proliferation and apoptosis by targeting the cell-cycle regulator CycE and the cell death inhibitor DIAP1. Studies that have incorporated large hpo clone mutations show that the Drosophila wings were larger than the normal, wild-type wings. In retinal sections, the hpo clones revealed that mutant ommatidia (components of the eyes, containing photoreceptors) appear to have the normal complement and arrangement of photoreceptor cells. The hpo mutant ommatidia showed to have more tissue between adjacent ommatidia.  This indicates that hpo plays a role in the regulation of organ size in tissues in multiple organ systems.

     Along with helping maintain a healthy tissue size, hpo is required for cell cycle exit and regulates the expression of CycE. Cyclin E is a paramount force that is needed for cell division (G1-S phase). However, over exposure of CycE is linked to many types of cancer, or can cause abnormalities such as impaired maturation. Needless to say, regulating this member of the cyclin family is crucial to the overall well being of the organism. Hpo regulates the exposure of CycE to maintain functionality of its job, but not too much to cause adverse affects on the cell system. 

      Finally, Hpo assists in the process of apoptosis. Cell death is triggered by regulated expression of the pro-apoptotic proteins Head involution defective(Hid)), Grim & Reaper. Hpo helps regulate and oversee this process, assuring that the pro-apoptotic proteins do not get out of control. It regulates DIAP1, an apoptosis inhibitor, which if too much DIAP1 is present, then the pro-apoptotic proteins cannot reduce the DIAP1 levels enough to activate caspases in the cells. So, once again, from the shadows, Hpo works diligently to ensure that the ratio of pro-apoptotic proteins/DIAP1 stays at an appropriate level to maximize cell death. 

     With all this knowledge, it is now understood why I call this gene a "slippery-slope" guardsman. It helps maintain balance and harmony between the three important cell processes. Without it, cells would get mutated, replicate, and will not go through apoptosis, leaving a horrible abomination in place of a uniquely formed organism, if even it survives. Hpo is only one of the three musketeers of cell regulation. Along with Sav and Wts, it keeps cells the size they need to be, when they need to proliferate, and when they need to die. 

Bibliography

   -Harvey, K., Pfleger, C., & Hariharan, I. (2003, July 15). The Drosophila Mst Ortholog, hippo, Restricts Growth and Cell Proliferation and Promotes Apoptosis. Redirecting. Retrieved June 6, 2014, from http://www.sciencedirect.com/science/article/pii/S0092867403005579

   -Ejsmont, R., & Hassan, B. The Little Fly that Could: Wizardry and Artistry of Drosophila Genomics. Genes, 2014, 385-414.

   -Huang, J., Wu, S., Barrera, J., Mathews, K., & Pan, D. The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP. Cell Press, 122, 421-434. Retrieved June 5, 2014, from http://www.sciencedirect.com/science/article/pii/S0092867405005520

   -Heallen, Todd, et al. "Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size." Science 332.6028 (2011): 458+. Academic OneFile. Web. 8 June 2014

   -Wu, Shian, Huang, Jianbin, Dong, Jixin, & Pan, Doujia. (2003, July 15). Hippo Encodes a Ste-20 Family Protein Kinase that Restricts Cell Proliferation and Promotes Apoptosis in Conjunction with Salvador and warts.