Or

Homozygous for mutant allele

Heterozygous for mutant allele

Homozygous for mutant allele

(b) Mitotic recombination

Heterozygous for mutant allele

Heterozygous for mutant allele

Chromosome duplication

Chromosome duplication

Recombination between homologous chromatids

Recombination between homologous chromatids

Normal 2:2

chromosome segregation

Homozygous for normal allele

Homozygous for mutant allele

Normal 2:2

chromosome segregation

Homozygous for normal allele

Homozygous for mutant allele

â–² FIGURE 23-11 Two mechanisms for loss of heterozygosity (LOH) of tumor-suppressor genes. A cell containing one normal and one mutant allele of a tumor-suppressor gene is generally phenotypically normal. (a) If formation of the mitotic spindle is defective, then the duplicated chromosomes bearing the normal and mutant alleles may segregate in an aberrant 3:1 ratio. A daughter cell that receives three chromosomes of a type will generally lose one, restoring the normal 2n chromosome number. Sometimes the resultant

Aberrations in Signaling Pathways That Control Development Are Associated with Many Cancers

During normal development secreted signals such as Wnt, TGFp, and Hedgehog (Hh) are frequently used to direct cells to particular developmental fates, which may include the property of rapid mitosis. The effects of such signals must be regulated so that growth is limited to the right time and place. Among the mechanisms available for reining in the effects of powerful developmental signals are inducible in-tracellular antagonists, receptor blockers, and competing signals (Chapter 15). Mutations that prevent such restraining cell will contain one normal and one mutant allele, but sometimes it will be homozygous for the mutant allele. Note that such aneuploidy (abnormal chromosome constitution) is generally damaging or lethal to cells that have to develop into the many complex structures of an organism, but can often be tolerated in clones of cells that have limited fates and duties. (b) Mitotic recombination between a chromosome with a wild-type and a mutant allele, followed by chromosome segregation, can produce a cell that contains two copies of the mutant allele.

mechanisms from operating are likely to be oncogenic, causing inappropriate or cancerous growth.

Hh signaling, which is used repeatedly during development to control cell fates, is a good example of a signaling pathway implicated in cancer induction. In the skin and cerebellum one of the human Hh proteins, Sonic hedgehog, stimulates cell division by binding to and inactivating a membrane protein called Patched1 (Ptc1) (see Figure 15-31). Loss-of-function mutations in ptcl permit cell proliferation in the absence of an Hh signal; thus ptcl is a tumor-suppressor gene. Not surprisingly, mutations in ptcl have been found in tumors of the skin and cerebellum in mice and

Hedgehog Patched) Smoothened

(Frizzled -â–ºDishevelled

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