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Oncogenic Mutations in Growth-Promoting Proteins

Genes encoding each class of cell regulatory protein depicted in Figure 23-8 have been identified as proto-oncogenes or tumor-suppressor genes. In this section we examine in more detail how mutations that result in the unregulated, constitutive activity of certain proteins or in their overproduction promote cell proliferation and transformation, thereby contributing to carcinogenesis. In each case we see how a rare cell that has undergone a very particular sort of mutation becomes abundant owing to its uncontrolled proliferation.

Oncogenic Receptors Can Promote Proliferation in the Absence of External Growth Factors

Although oncogenes theoretically could arise from mutations in genes encoding growth-promoting signaling molecules, this rarely occurs. In fact, only one such naturally occurring oncogene, sis, has been discovered. The sis oncogene, which encodes a type of platelet-derived growth factor (PDGF), can aberrantly autostimulate proliferation of cells that normally express the PDGF receptor.

In contrast, oncogenes encoding cell-surface receptors that transduce growth-promoting signals have been associated with several types of cancer. The receptors for many such growth factors have intrinsic protein-tyrosine kinase activity in their cytosolic domains, an activity that is quiescent until activated. Ligand binding to the external domains of these receptor tyrosine kinases (RTKs) leads to their dimer-ization and activation of their kinase activity, initiating an in-tracellular signaling pathway that ultimately promotes proliferation.

In some cases, a point mutation changes a normal RTK into one that dimerizes and is constitutively active in the absence of ligand. For instance, a single point mutation converts the normal Her2 receptor into the Neu oncoprotein, which is an initiator of certain mouse cancers (Figure 23-14, left). Similarly, human tumors called multiple endocrine neo-plasia type 2 produce a constitutively active dimeric Glia-derived neurotrophic factor (GDNF) receptor that results

Proto-oncogene receptor proteins

Her2 receptor EGF receptor

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Cytosol

Exterior

Cytosol

s Valine

s Valine

Deletion

Inactive w receptor tyrosine kinase

Oncogenic mutations

Deletion

Neu oncoprotein

Exterior Cytosol

Neu oncoprotein

Exterior Cytosol

Glutamine

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