Aberrant Signalling and Cancer

Extracellular growth factors are proteins that control mammalian cell proliferation and/or differentiation through the binding of receptors on cell surfaces to initiate a cascade of events. Many growth factors dictate the balance between proliferation and cell death within organs. For normal cells to remain viable, they require stimulation from growth factors. However, when cells become transformed and tumorigenic, this requirement is circumvented as their growth and survival pathways have become hyperactivated by oncogenes, thereby freeing them from the need for exogenous growth factor signals.

DNA damage through environmental factors, which mutate DNA, and inherited genetic mutations have been shown to be involved in the production of oncogenes that lead to cell transformation and ultimately cancer. Oncogenes arise through several mechanisms.

(1) DNA rearrangements, the most common mutation as seen in the translocation of c-myc to sites where it is over-expressed, bcr-abl fusion as in the case of chronic myeloid leukemia (CML) or proteins may be truncated making them constitutively active.

(2) Gene amplification.

(3) Point mutations, e.g. mutations at position 12 and 61 in ras making it constitutively active.

(4) Integration of viral DNA next to a proto-oncogene.

Through these processes, normal cellular genes may be inappropriately expressed resulting in loss of control over the cell-cycle then cell transformation. Oncogenes encode proteins involved in cell-cycle control or have high homology with TK growth factor receptors (e.g. v-fms, v-ros, v-sis, v-erb B), and may code for factors involved at all the important mitogenic stages. Another important oncogene src (non-receptor TK) has sequence homology with EGFR and is able to activate over 50 distinct substrates through its TK. Permanent activation/over-expression of scr has been identified in many cancers. While many of these oncogenes are membrane associated, myc, myb and fos act on transcription in the nucleus. Unlike myc and ras, many oncogenes are tissue-specific and their role in cancer development and progression has been the source of targets for cancer therapeutics, since different oncogenes act at different stages. In addition to gain of function mutations mentioned, loss of function mutations particularly with genes that carryout DNA-repair, and tumour suppressors such as the retinoblastoma protein - pRB, p53, phosphatase and tensin homolog - PTEN, BRACA etc. also give rise to cancers. PTEN is mutated in many cancers as it dephosphorylates PIP3 in PI3K/PKB signalling controlling cell proliferation and apoptosis. Similarly, p53, which coordinates signals to determine whether or not a cell goes through the cell-cycle or is destroyed, is frequently mutated in many cancers. Mutations in genes accounting for more than 1% of the human genome contribute to cancer, which makes these genes attractive targets for drug development.

By Seian S. Morrison. Profit Vault changed my views on life. http://www.profitvault.co/index-5081.html

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