When activated, RTKs in turn activate the Ras, Raf, MEK, MAPK, MKK, ERK, Fos, JNKs, and Jun pathway, which can lead to the induction of ARF via gene upregulation. ARF in turn suppresses mdm2, a suppressor of p53 activity. The resulting increase in p53 activity can induce Bax, Mt, and thus apoptosis.
4. Adenomatous familial polyposis is caused by a truncated APC protein, which results from inherited mutations in the APC gene (Segditsas and Tomlinson, 2006). However, the activity of the wild-type or normal APC allele is usually sufficient to maintain tumor suppressor activity. For this reason, and because the wild-type allele is often found to have acquired somatic mutations, it is assumed that both alleles must be mutated before tumors can form. The vast majority of mutations found in colorectal tumors have retained 0 to 3 20-amino acid repeats, suggesting APC proteins that retain some ?-catenin binding activity result most often in tumor formation. The following describes the steps believed to occur from inheriting a mutated APC allele to the formation of cancer:
a. An APC allele with a mutation that truncates the expressed protein after the second 20-amino acid repeat domain is inherited.
b. The other normal APC...
The loss of heterozygosity leads to decreased tumor suppressor activity, because the APC proteins are limited in their ability to bind and degrade ? -- catenin.
d. In the presence of Wnt signaling, the translocation of increased levels of ? -- catenin to the nucleus results in proliferation and transformation. The 'just right' hypothesis suggests that limited APC tumor suppressor activity conferred by the inherited and somatic mutations allows Wnt signaling to be just right for tumor development. In support of this argument, complete loss of APC is not a common mutation found in colorectal tumors.
References
Libby, Peter, Ridker, Paul M., and Hansson, Goran K. (2011). Progress and challenges in translating the biology of atherosclerosis. Nature, 473, 317-325.
Segditsas, S. And Tomlinson, I. (2006). Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene, 25, 7531-7537.
Minde, David P., Anvarian, Zeinab, Rudiger, Stefan G.D., and Maurice, Madelon M. (2011). Messing up disorder: How do missense mutations in the tumor suppressor protein APC lead to cancer? Molecular Cancer, 10, 1-9.
