The following is the start of my cell biology capstone research as a Biology major, before I switched to English. I researched gene mutations being linked to causing colon cancer.
Effect of B-Catenin and Cyclin D1 on WNT Signaling Pathway Associated with Colon Cancer
May 1, 2012
“A paper submitted to the faculty in Biology at Presbyterian College in partial fulfillment of the requirements for B399: Scientific Writing & Presentation”
To fully understand the effects that the protein B-catenin and the kinase activator cyclin d1 have on the WNT signaling pathway, one must first fully comprehend each of these individual components and what their functions are. The WNT signaling pathway is a canonical pathway in the body responsible for cell growth and differentiation. Activation of WNT signaling results in gene mutations, which ultimately lead to tumor formation (Fodde et al. 2007). This pathway includes a transmembrane protein receptor for WNT. When bound to this receptor, the destruction complex, a multiprotein complex that binds to and phosphorylates B-catenin, thereby targeting degradation of B-catenin, is inhibited and the pathway is on (Polakis 2011). Transcriptional co activators are stabilizing B-catenin, allowing transcription to occur inside the nucleus, as shown in Figure 1.
Figure 1 WNT Signaling Pathway in Action (after Polakis 2011).
When a protein called dkk is acting as an antagonist and blocking the docking site for WNT, there are problems. The destruction complex described above is then activated and can bind to and degrade B-catenin, suppressing its ability to transcribe amino acids in the nucleus, again shown in Figure 1. Also activated simultaneously are a set of gene repressors in the place of B-catenin’s transcriptional co activators. Figure 1 shows both the activated WNT pathway, with B-catenin effectively transcribing genes, and the deactivated pathway, where B-catenin is degraded by the destruction complex (Polakis 2011).
The two main factors of the WNT pathway examined in this research are B-catenin and cyclin d1. Since B-catenin is directly involved in gene transcription, there is a link between its role in the pathway with other proto-oncogenes, genes that have the ability to cause cancer if mutated, to causing cancer (Polakis 2011). There is evidence that when B-catenin is linked with the proto-oncogene APC, a tumor suppressor which is deactivated when B-catenin is actively transcribing, and activated when B-catenin is suppressed, mutant colorectal cancer cells form due to the downregulation of B-catenin by APC; meaning that these two factors have been linked to forming cancerous cells and more importantly, B-catenin is vital for prohibiting cancerous cells from forming (Polakis 2011). Cyclin d1 is a target gene of B-catenin (Vlad-Fiegen 2012). Cyclin d1 is also a proto-oncogene, and helps regulate cell growth and differentiation, specifically at the G1/S phase of the cell cycle. This research examines specifically the role that cyclin d1 has on colorectal carcinoma cell migration. Cyclin d1 promotes the migration of cancerous cells when present and uninhibited in the WNT pathway. Cyclin d1 facilitates tumor cell migration by decreasing cell adhesion, forming gaps between these cells through which carcinogenic cells can migrate (Vlad-Fiegen 2012). While there are many more activators, transcription factors and gene suppressors that play an active role in linking the WNT pathway to cancer, B-catenin and cyclin d1 are by far the biggest components for causing colorectal cancer.
Cancer is the continuous growth of malignancy. Malignant tumors form and are metastasized to other areas, caused by uncontrolled cell growth and differentiation. Since the WNT signaling pathway is the major pathway associated with cell growth and development, there is undoubtedly a connection between a disease caused by uninhibited cell differentiation and this pathway. More specifically, there is a direct correlation between mutations in B-catenin and upregulation of cyclin d1 on the formation and migration of colorectal carcinoma cells, as described above. It is thought that if oncologists completely understand all mechanisms involved in tumor formation, specifically for one type of cancer, such as colorectal cancer, there will also be a proposed way to stop this disease, or at the very least, cure it in those individuals already suffering. If the role of two proto-oncogenes in tumor formation of colorectal carcinogenic cells is understood, there is hope that there will be a way to prevent these cells from metastasizing into tumors, and to ultimately prevent cancer.
Most research has been conducted to show not only a connection between B-catenin and cyclin d1 and WNT, but also the effects of APC, another proto-oncogene, as well as other genes in the destruction complex. It would be interesting to see if any of the transcription factors inside the nucleus have any effect on mutations when B-catenin is effectively transcribing amino acids, uninhibited by the destruction complex. Possible further research could be done to determine the effects of these same proto-oncogenes have the same, or any effect on other types of cancer cells besides colorectal. Since the WNT pathway regulates cell proliferation, an alteration in such a pathway causes excessive proliferation leading to tumor formation. The aim of this research is to examine the factors that lead to an alteration in the WNT pathway, B-catenin and cyclin d1, with the intention of ultimately curing cancer.
Fodde R, Brabletz T. 2007. Wnt/B-catenin signaling in cancer stemness and malignant behavior. In: Current Opinion in Cell Biology. Carl-Henrik Heldin, Peter ten Dijke, editors. Current Opinion in Cell Biology, 19. Germany: Elsevier. Pp 150-158. http://www.sciencedirect.com.libproxy.presby.edu/science/article/pii/S095506740700021X
Polakis P. 2011. An Introduction to Wnt Signaling. In: Targeting the Wnt Pathway in Cancer. K.H. Goss, M. Kahn, editors. San Fransisco: Springer Science and Business LLC. Pp 1-12. http://www.springerlink.com.libproxy.presby.edu/content/n0482j8670r35013/?MUD =MP
Vlad-Fiegen A, Langerak A, Eberth S, Mueller O. 2012. The Wnt pathway destabilizes adherens junction and promotes cell migration via B-catenin and its target gene cyclin d1. In: FEBS Open Bio. Germany: Elsevier. Pp 26-31. http://www.sciencedirect.com/science/article/pii/S2211546312000071http://www.sciencedirect.com/science/article/pii/S2211546312000071