RAS signalling in the colorectum in health and disease.
RAS proteins act as molecular switches between several homeostatic inputs and signal transduction pathways that regulate important cellular processes including cell growth, differentiation and survival. Activating mutations change the function of normal proto-oncogenic RAS proteins to oncogenic RAS proteins that trigger a wide range of downstream effectors altering expression of transcription factors that together stimulate cell proliferation and modulate apoptosis and differentiation. RAS genes are amongst the most frequently mutated genes in human cancers, in particular KRAS is mutated in 40-50% of colorectal cancers. Mutation of this gene has a significant impact on treatment management and patients' survival, particularly in relation to anti-EGFR therapy, which is only effective in KRAS wild-type cases. Here, we discuss the regulation of KRAS signalling in the colorectum, some of the post-transcriptional and post-translational modifications that control its activity, the mutations and other DNA alterations that are found in this tumour type and the implications that they have for disease progression and current drug treatments.
Department of Systems Biology, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
George
G
Poulogiannis
Feijun
F
Luo
Mark J
MJ
Arends
D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D003106:Colon / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D011499:Protein Processing, Post-Translational; D012007:Rectum / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D035683:MicroRNAs; D018631:ras Proteins