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Aberrant Signalling and Cancer

عبدالرحمن حسن علي
مؤســس المنتدى
مؤســس المنتدى
الجنسية :
عدد المشاركات عدد المشاركات : 16048
تقييم المشترين تقييم المشترين : 49
واتساب واتساب : 201289700022
معاينة صفحة البيانات الشخصي للعضو

في الإثنين 22 أغسطس - 18:39

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
(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.
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.

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