muation and cancer /causes of mutation/EFFECTS OF MUATION

1. Cancer and Gene Mutation

2. (a) Proper external cues for normal cell survival and proliferation.

3. (b) Proper external cues for normal cell death or inhibition of proliferation.

4. (c) Proper external cues for normal cell survival without proliferation.

5. (d) Self-generated survival and proliferation signals in cancer cells.

6.  the normal regulation of cell numbers can be regarded as
 the interplay between mechanisms that control cell proliferation and
those that control cell death.
 Cell proliferation is controlled by the mitotic cell cycle
whereas cell death is achieved through a mechanism called
programmed cell death, or apoptosis.

7. In both cases, sequential biochemical events depend
on the successful occurrence of prior events.
In the cell cycle, failsafe mechanisms—called
checkpoints—prevent the cell cycle from progressing
until prior events have been successfully completed.

8. Cell Cycle Proliferation

9. The cell-proliferation
machinery of the cell cycle

10.  The engines that drive the cell cycle from one step to the next are a series
of protein complexes called CDK-cyclin complexes.
 Ultimately, going to the next step requires the activation of genes whose
protein products are necessary for the next phase of the cell cycle.
 This activation occurs through the turning on of transcription factors by
the CDK-cyclin complexes.
 Consider, for example, the CDK-cyclin complex active during G1, which
takes the cell cycle into the S phase, when DNA is synthesized.
Cyclins and cyclin-dependent protein kinases

11. Cyclins
 Every eukaryote has a family of structurally and functionally
related cyclin proteins.
 Cyclins are so named because each is present in the cell only
during one or more defined segments of the cell cycle.
 The appearance of a specific cyclin is the result of the
activity of the preceding CDK-cyclin complex, which leads to
the activation of a transcription factor for the new cyclin.

12. Cyclin-dependent protein kinases (CDKs)
 Cyclin-dependent protein kinases are another family of
structurally and functionally related proteins.
 Kinases are enzymes that add phosphate groups to target
substrates; for protein kinases, such as CDKs, the substrates
are the side groups of specific amino acids on specific
proteins.
 Each CDK catalyzes the phosphorylation of specific serine
and threonine residues belonging to one or more unique
target proteins. Becoming phosphorylated changes the
activity of the target protein.

13. Phosphorylation of target proteins by the CDK-cyclin complex.

14.  Sequential activation of different CDK-cyclin complexes
ultimately controls progression of the cell cycle.

15. Checkpoints as brakes
on cell-cycle progression
Fail-safe systems called checkpoints ensure that the
cell cycle does not progress until the cell has
completed all prior events necessary to assure its
survival through the next steps.

16. How do checkpoints act as brakes on the cell
cycle?
They activate proteins that can inhibit the protein
kinase activity of one of the CDK-cyclin complexes.
In this way, the cell cycle can be held in check until
the checkpoint monitoring mechanisms give a
“green light,” indicating that the cell is properly
prepared to proceed to the next phase of the cycle.

17. Inhibitory control of the progression of the cell cycle in mammals.

18. Programmed Cell Death (Apoptosis)

19. The machinery
of programmed cell death
 In multicellular organisms, systems have evolved to eliminate damaged
(and hence potentially harmful) cells by a self-destruct and disposal
mechanism called programmed cell death or apoptosis.
 This self-destruct mechanism can be activated under many different
circumstances, such as cells that are no longer needed for development.
 Programmed cell death is mediated by a sequential cascade of
proteolysis events that activate enzymes that destroy several key targeted
cellular components.
 In all cases, however, the events in apoptosis seem to be the same
(Figure).

20. Sequence of events in apoptosis
First, the DNA of the chromosomes is fragmented, organelle structure is disrupted,
and the cell loses its normal shape and becomes spherical.

21. Then, the cell breaks up into small fragments called apoptotic bodies, which are
phagocytosed (literally, eaten up) by motile scavenger cells.

22.  The engines of self-destruction are a series of enzymes called
caspases, which is short for cysteine containing aspartate-specific
proteases.
 Proteases are enzymes that cleave other proteins.
 The general term for such cleavage of proteins is proteolysis.
 Each caspase is a protease rich in cysteines: when activated, it
cleaves certain target proteins at a specific aspartate.
 These target proteins initiate fragmentation of DNA, disruption of
organelles, and other events that characterize apoptosis.

23. Programmed cell death is mediated by a sequential
cascade of proteolysis events that activate enzymes
that destroy several key targeted cellular
components.

24. Cancer and Gene mutation

25. How cancer cells differ from normal cells
Cancer cells typically differ from their normal
neighbors by a host of phenotypic characters, such
as:
 rapid division rate
ability to invade new cellular territories
high metabolic rate
abnormal shape

26. Normal cells and cell transformed by an oncogene.
(a) A normal cell line. Note the organized monolayer structure of the cells.
(b) A mutant cell line. Note how the cells are rounder and piled up on one another.

27.  Tumors arise from a sequence of mutational events that lead
to uncontrolled proliferation and cellular immortality.
 Generally, cancer is being due to the accumulation of multiple
mutations in a single cell that cause it to proliferate out of
control.
 Some of those mutations may be transmitted from the
parents through the germ line.
 But most arise de novo in the somatic-cell lineage of a
particular cell.

28. A tumor does not arise as a result of a single genetic
event but rather as the result of multiple hits;
 that is, several mutations must arise within a single cell for
it to become cancerous.
 Occasionally, a single mutation is powerful enough
to guarantee that a cancer will form.

29. Oncogenes and tumor suppressor genes
Two of the main types of genes that play a
role in cancer are
 oncogenes
tumor suppressor genes

30. Oncogenes
 The gene in its normal, unmutated form is called a proto-
oncogene.
 Proto-oncogenes are genes that normally help cells grow.
 When a proto-oncogene mutates (changes) or there are too many
copies of it, it becomes a "bad" gene that can become
permanently turned on or activated when it is not supposed to
be.
 When this happens, the cell grows out of control, which can lead
to cancer. This bad gene is called an oncogene.

31. Tumor suppressor genes
Tumor suppressor genes are normal genes that slow
down cell division, repair DNA mistakes, or tell cells
when to die (a process known
as apoptosis or programmed cell death).
 When tumor suppressor genes don't work properly,
cells can grow out of control, which can lead to
cancer.

32. In regard to how mutations act within the cancer cell,
two general kinds are associated with tumors:
 oncogene mutations
mutations in tumor-suppressor genes

33. Oncogene mutations
 Oncogene mutations act in the cancer cell as gain-of
function dominant mutations. That is, the mutation need be
present as only one allele to contribute to tumor formation.
 Gain-of-function mutation: A mutation that confers new or
enhanced activity on a protein.
 When the mutation is present in protein-coding DNA, the
oncogene causes a structural change in the encoded
protein.
 When the mutation is present in a regulatory element, the
oncogene causes a structurally normal protein to be
misregulated.

34. Mutations in tumor-suppressor genes
 Mutations in tumor-suppressor genes that promote tumor
formation are loss-of-function recessive mutations. That is,
for cancer to occur, both alleles of the gene must encode
gene products having reduced or no residual activity (that is,
they are null mutations).
 Loss-of-function mutations, which are more common, result
in reduced or abolished protein function.

35.  An important difference between oncogenes and tumor
suppressor genes is that oncogenes result from
the permanent activation (turning on) of proto-oncogenes,
but tumor suppressor genes cause cancer when they
are inactivated (turned off).
The proteins that oncogenes encode are activated
in tumor cells, whereas the proteins that tumor
suppressor genes encode are inactivated.

36. Genes that become oncogenes are genes encoding
proteins that positively control (turn on) the cell cycle
or negatively control (block) apoptosis.
 The mutant proteins are now active even in the absence of
the appropriate activation signals. As a consequence,
oncogenes act either to increase the rate of cell
proliferation or to prevent apoptosis.

37. On the other hand, tumor-suppressor genes
encode proteins that arrest the cell cycle or
induce apoptosis; in these cases, the cell loses
a brake that can stop cell proliferation.

38. Many proteins that are altered by cancer-producing mutations take part in intercellular
communication and the regulation of the cell cycle and apoptosis (Table 17-1).

39. Thanks for your attention 