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Chapter Outline
Cancer: A Genetic Disease Oncogenes Tumor Suppressor Genes Genetic Pathways to Cancer Tumors in Plants
John Wiley & Sons, Inc.
Cancer
Cancers arise when critical genes are mutated, causing unregulated proliferation of cells. These rapidly dividing cells pile up on top of each other to form a tumor. When cells detach from the tumor and invade surrounding tissues, the tumor is malignant and may form secondary tumors at other locations in a process called metastasis. A tumor whose cells do not invade surrounding tissues is benign.
Location/distribution
Telomere maintenance
Constant signal to divide
independent
Invasion Metastasis
Matrix
Why? How?
Basal lamina
Loss of cell surface proteins involve in cell-cell adhesion E-cadherin Increased Motility signaling molecules, chemoattractants, protease activator (plasminogen
plasmin)
Cancers
The CDKs phosphorylate target proteins but are inactive unless they are associated with a cyclin protein. Cell cycling requires the alternate formation and degradation of cyclin/CDK complexes.
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/A
S cyclins
bubble
Autoproteolysis
ATP
proteolysis
Oncogenes
the overexpression of certain genes the abnormal activity of certain genes their mutant protein products.
Human?
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Proto-Oncogenes
The proteins encoded by viral oncogenes are similar to cellular proteins with important regulatory functions. These cellular homologues are called protooncogenes or normal cellular genes. The normal c-oncogenes have introns; the viral v-oncogenes often lack introns. From c-onco to v-onco.. Replicationdefective viruses John Wiley & Sons, Inc.
Replication-defective virus
The mutant c-H-ras protein has a mutation that impairs its ability to hydrolyze GTP. This keeps the mutant protein in an active signaling mode and causes it to stimulate cell division.
Mutant versions of c-ras have been found in John Wiley & Sons, Inc. many types of tumors.
Most dominant activating mutations in cellular oncogenes occur spontaneously in somatic cells, not in the germline.
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8p21.1
The proteins encoded by tumor suppressor genes are involved in cell division, cell differentiation, programmed cell death, DNA repair.
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Most mutations in that inactivate p53 are in the DNAbinding domain (DBD) and impair its ability to bind enhancer sequences in its target genes. Mutations in this domain are lost-of-function.
OD: homo-oligomerazation domain. Mutations in this domain are dominant negative. TAD: transcriptional activation domain
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[ increase ] p-p53
pAPC
As mutations accumulate and cells become unregulated, genetic instability increases the likelihood that the cells will develop the hallmarks of cancer.
Bacteria genetically engineer plants to control their differentiation (tumorigenic) and production of opines that can only be catabolized by the infecting Agrobacterium strain.
R1 R2 HOOC-C-NH-C-COOH H H
T-DNA is generated when a nick at the right boundary creates a primer for synthesis of a new DNA strand. The preexisting single-strand that is displaced by the new synthesis is transferred to the plant cell nucleus. Transfer is terminated when DNA synthesis reaches a nick at the left boundary.
The T-DNA is transferred as a complex of single-stranded DNA with the VirE2 single-strand binding protein.
The single stranded T-DNA is converted into double-stranded DNA and integrated into the plant genome. The mechanism of integration is not known. T-DNA can be used to transfer genes into a plant nucleus (transformation).