1. Chapter 18- Gene Regulation Part 3

2. The Life Cycle of Drosophila
In Drosophila, cytoplasmic determinants in the unfertilized egg determine the axes before fertilization
After fertilization, the embryo develops into a segmented larva with three larval stages

3. Figure 18.17 Key developmental events in the life cycle of Drosophila
Head
Thorax
Abdomen
0.5 mm
Dorsal
Right
BODY
AXES
Anterior
Posterior
Left
Ventral
(a) Adult
Follicle cell 1
Egg cell
developing within
ovarian follicle
Nucleus
Egg
cell
Nurse cell 2
Unfertilized egg
Egg
shell
Depleted
nurse cells
Fertilization
Laying of egg 3
Fertilized egg
Figure Key developmental events in the life cycle of Drosophila
Embryonic
development 4
Segmented
embryo
0.1 mm
Body
segments
Hatching 5
Larval stage
(b) Development from egg to larva

4. Head Thorax Abdomen 0.5 mm Dorsal Right BODY AXES Anterior Posterior
Fig a
Head
Thorax
Abdomen
0.5 mm
Dorsal
Right
BODY
AXES
Anterior
Posterior
Figure Key developmental events in the life cycle of Drosophila
Left
Ventral
(a) Adult

5. (b) Development from egg to larva
Fig b
Follicle cell 1
Egg cell
developing within
ovarian follicle
Nucleus
Egg
cell
Nurse cell 2
Unfertilized egg
Egg
shell
Depleted
nurse cells
Fertilization
Laying of egg 3
Fertilized egg
Embryonic
development
Figure Key developmental events in the life cycle of Drosophila 4
Segmented
embryo
0.1 mm
Body
segments
Hatching 5
Larval stage
(b) Development from egg to larva

6. Genetic Analysis of Early Development: Scientific Inquiry
Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus won a Nobel 1995 Prize for decoding pattern formation in Drosophila
Lewis demonstrated that genes direct the developmental process

7. Eye Leg Antenna Wild type Mutant Fig. 18-18
Figure Abnormal pattern formation in Drosophila
Wild type
Mutant

8. Eye Antenna Wild type Fig. 18-18a
Figure Abnormal pattern formation in Drosophila
Antenna
Wild type

9. Fig b
Figure Abnormal pattern formation in Drosophila
Leg
Mutant

10. Nüsslein-Volhard and Wieschaus studied segment formation
They created mutants, conducted breeding experiments, and looked for corresponding genes
Breeding experiments were complicated by embryonic lethals, embryos with lethal mutations
They found 120 genes essential for normal segmentation

11. Animation: Development of Head-Tail Axis in Fruit Flies
Axis Establishment
Maternal effect genes encode for cytoplasmic determinants that initially establish the axes of the body of Drosophila
These maternal effect genes are also called egg-polarity genes because they control orientation of the egg and consequently the fly
Animation: Development of Head-Tail Axis in Fruit Flies

12. Bicoid: A Morphogen Determining Head
Structures
One maternal effect gene, the bicoid gene, affects the front half of the body
An embryo whose mother has a mutant bicoid gene lacks the front half of its body and has duplicate posterior structures at both ends

13. Fig
EXPERIMENT
Tail
Head T1 T2 A8 T3 A7 A1 A2 A3 A4 A5 A6
Wild-type larva
Tail
Tail A8 A8 A7 A6 A7
Mutant larva (bicoid)
RESULTS
Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly?
Fertilization,
translation
of bicoid
mRNA
100 µm
Anterior end
Bicoid mRNA in mature
unfertilized egg
Bicoid protein in early
embryo
CONCLUSION
Nurse cells
Egg
bicoid mRNA
Developing egg
Bicoid mRNA in mature unfertilized egg
Bicoid protein in early embryo

14. EXPERIMENT Tail Head Wild-type larva Tail Tail Mutant larva (bicoid)
Fig a
EXPERIMENT
Tail
Head A8 T1 T2 T3 A7 A1 A6 A2 A3 A4 A5
Wild-type larva
Tail
Tail
Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly? A8 A8 A7 A7 A6
Mutant larva (bicoid)

15. RESULTS Anterior end Bicoid mRNA in mature unfertilized egg
Fig b
RESULTS
Fertilization,
translation
of bicoid
mRNA
100 µm
Anterior end
Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly?
Bicoid mRNA in mature
unfertilized egg
Bicoid protein in early
embryo

16. CONCLUSION Nurse cells Egg bicoid mRNA Developing egg
Fig c
CONCLUSION
Nurse cells
Egg
bicoid mRNA
Developing egg
Figure Is Bicoid a morphogen that determines the anterior end of a fruit fly?
Bicoid mRNA in mature
unfertilized egg
Bicoid protein
in early embryo

17. This phenotype suggests that the product of the mother’s bicoid gene is concentrated at the future anterior end
This hypothesis is an example of the gradient hypothesis, in which gradients of substances called morphogens establish an embryo’s axes and other features

18. The bicoid research is important for three reasons:
– It identified a specific protein required for some early steps in pattern formation
– It increased understanding of the mother’s role in embryo development
– It demonstrated a key developmental principle that a gradient of molecules can determine polarity and position in the embryo

19. Concept 18.5: Cancer results from genetic changes that affect cell cycle control
The gene regulation systems that go wrong during cancer are the very same systems involved in embryonic development

20. Types of Genes Associated with Cancer
Cancer can be caused by mutations to genes that regulate cell growth and division
Tumor viruses can cause cancer in animals including humans

21. Oncogenes and Proto-Oncogenes
Oncogenes are cancer-causing genes
Proto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division
Conversion of a proto-oncogene to an oncogene can lead to abnormal stimulation of the cell cycle

22. within a control element within the gene
Fig
Proto-oncogene
DNA
Translocation or
transposition:
Gene amplification:
Point mutation:
within a control element
within the gene
New
promoter
Oncogene
Oncogene
Figure Genetic changes that can turn proto-oncogenes into oncogenes
Normal growth-
stimulating
protein in excess
Normal growth-stimulating
protein in excess
Normal growth-
stimulating
protein in excess
Hyperactive or
degradation-
resistant protein

23. Proto-oncogenes can be converted to oncogenes by
Movement of DNA within the genome: if it ends up near an active promoter, transcription may increase
Amplification of a proto-oncogene: increases the number of copies of the gene
Point mutations in the proto-oncogene or its control elements: causes an increase in gene expression

24. Tumor-Suppressor Genes
Tumor-suppressor genes help prevent uncontrolled cell growth
Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset
Tumor-suppressor proteins
Repair damaged DNA
Control cell adhesion
Inhibit the cell cycle in the cell-signaling pathway

25. Interference with Normal Cell-Signaling Pathways
Mutations in the ras proto-oncogene and p53 tumor-suppressor gene are common in human cancers
Mutations in the ras gene can lead to production of a hyperactive Ras protein and increased cell division

26. Figure 18.21 Signaling pathways that regulate cell division
Growth
factor
MUTATION
Hyperactive
Ras protein
(product of
oncogene)
issues
signals
on its own
Ras 3
G protein
GTP
Ras
GTP 2
Receptor 4
Protein kinases
(phosphorylation
cascade)
NUCLEUS 5
Transcription
factor (activator)
DNA
Gene expression
Protein that
stimulates
the cell cycle
(a) Cell cycle–stimulating pathway 2
Protein kinases
MUTATION
Defective or
missing
transcription
factor, such
as p53, cannot
activate UV
light 3
Active
form
of p53 1
DNA damage
in genome
Figure Signaling pathways that regulate cell division
DNA
Protein that
inhibits
the cell cycle
(b) Cell cycle–inhibiting pathway
EFFECTS OF MUTATIONS
Protein
overexpressed
Protein absent
Cell cycle
overstimulated
Increased cell
division
Cell cycle not
inhibited
(c) Effects of mutations

27. (a) Cell cycle–stimulating pathway
Fig a 1
Growth
factor 1
MUTATION
Hyperactive
Ras protein
(product of
oncogene)
issues
signals
on its own
Ras 3
G protein
GTP
Ras
GTP 2
Receptor 4
Protein kinases
(phosphorylation
cascade)
NUCLEUS 5
Transcription
factor (activator)
DNA
Figure Signaling pathways that regulate cell division
Gene expression
Protein that
stimulates
the cell cycle
(a) Cell cycle–stimulating pathway

28. (b) Cell cycle–inhibiting pathway
Fig b 2
Protein kinases
MUTATION
Defective or
missing
transcription
factor, such
as p53, cannot
activate 3
Active
form
of p53 UV
light 1
DNA damage
in genome
DNA
Figure Signaling pathways that regulate cell division
Protein that
inhibits
the cell cycle
(b) Cell cycle–inhibiting pathway

29. (c) Effects of mutations
Fig c
EFFECTS OF MUTATIONS
Protein
overexpressed
Protein absent
Cell cycle
overstimulated
Increased cell
division
Cell cycle not
inhibited
Figure Signaling pathways that regulate cell division
(c) Effects of mutations

30. Suppression of the cell cycle can be important in the case of damage to a cell’s DNA; p53 prevents a cell from passing on mutations due to DNA damage
Mutations in the p53 gene prevent suppression of the cell cycle

31. The Multistep Model of Cancer Development
Multiple mutations are generally needed for full-fledged cancer; thus the incidence increases with age
At the DNA level, a cancerous cell is usually characterized by at least one active oncogene and the mutation of several tumor-suppressor genes

32. EFFECTS OF MUTATIONS Fig. 18-22
Colon
EFFECTS OF MUTATIONS
Loss of tumor-
suppressor gene
APC (or other) 1
Activation of
ras oncogene 2
Loss of
tumor-suppressor
gene p53 4
Colon wall
Loss of
tumor-suppressor
gene DCC 3
Additional
mutations 5
Figure A multistep model for the development of colorectal cancer
Normal colon
epithelial cells
Small benign
growth (polyp)
Larger benign
growth (adenoma)
Malignant tumor
(carcinoma)

33. Colon Colon wall Normal colon epithelial cells Fig. 18-22a
Figure A multistep model for the development of colorectal cancer
Normal colon
epithelial cells

34. 1 Small benign growth (polyp) Loss of tumor- suppressor gene
Fig b
Loss of tumor-
suppressor gene
APC (or other) 1
Small benign
growth (polyp)
Figure A multistep model for the development of colorectal cancer

35. Activation of ras oncogene 2 3 Larger benign growth (adenoma) Loss of
Fig c
Activation of
ras oncogene 2
Loss of
tumor-suppressor
gene DCC 3
Larger benign
growth (adenoma)
Figure A multistep model for the development of colorectal cancer

36. Additional mutations Malignant tumor (carcinoma) Loss of 4
Fig d
Loss of
tumor-suppressor
gene p53 4
Additional
mutations 5
Malignant tumor
(carcinoma)
Figure A multistep model for the development of colorectal cancer

37. Inherited Predisposition and Other Factors Contributing to Cancer
Individuals can inherit oncogenes or mutant alleles of tumor-suppressor genes
Inherited mutations in the tumor-suppressor gene adenomatous polyposis coli are common in individuals with colorectal cancer
Mutations in the BRCA1 or BRCA2 gene are found in at least half of inherited breast cancers

38. Fig
Figure Tracking the molecular basis of breast cancer

39. Operon Promoter Genes A B C Operator RNA polymerase A B C Polypeptides
Fig. 18-UN1
Operon
Promoter
Genes A B C
Operator
RNA
polymerase
Fig. 18-UN1 A B C
Polypeptides

40. no corepressor present Corepressor
Fig. 18-UN2
Genes expressed
Genes not expressed
Promoter
Genes
Operator
Active repressor:
corepressor bound
Inactive repressor:
no corepressor present
Corepressor
Fig. 18-UN2

41. Genes not expressed Genes expressed Promoter Operator Genes
Fig. 18-UN3
Genes not expressed
Genes expressed
Promoter
Operator
Genes
Fig. 18-UN2
Active repressor:
no inducer present
Inactive repressor:
inducer bound
Fig. 18-UN3

42. Protein processing and degradation
Fig. 18-UN4
Chromatin modification
Transcription
• Genes in highly compacted
chromatin are generally not
transcribed.
• Regulation of transcription initiation:
DNA control elements bind specific
transcription factors.
• Histone acetylation seems to
loosen chromatin structure,
enhancing transcription.
Bending of the DNA enables activators to
contact proteins at the promoter, initiating
transcription.
• DNA methylation generally
reduces transcription.
• Coordinate regulation:
Enhancer for
liver-specific genes
Enhancer for
lens-specific genes
Chromatin modification
Transcription
RNA processing
• Alternative RNA splicing:
RNA processing
Primary RNA
transcript
mRNA
degradation
Translation
mRNA or
Fig. 18-UN4
Protein processing
and degradation
Translation
• Initiation of translation can be controlled
via regulation of initiation factors.
mRNA degradation
• Each mRNA has a
characteristic life span,
determined in part by
sequences in the 5 and
3 UTRs.
Protein processing and degradation
• Protein processing and
degradation by proteasomes
are subject to regulation.

43. Chromatin modification
Fig. 18-UN5
Chromatin modification
• Small RNAs can promote the formation of
heterochromatin in certain regions, blocking
transcription.
Chromatin modification
Transcription
Translation
RNA processing
• miRNA or siRNA can block the translation
of specific mRNAs.
mRNA
degradation
Translation
Protein processing
and degradation
Fig. 18-UN5
mRNA degradation
• miRNA or siRNA can target specific mRNAs
for destruction.

44. Enhancer Promoter Gene 1 Gene 2 Gene 3 Gene 4 Gene 5
Fig. 18-UN6
Enhancer
Promoter
Gene 1
Gene 2
Gene 3
Fig. 18-UN6
Gene 4
Gene 5

45. Fig. 18-UN7
Fig. 18-UN7

46. Fig. 18-UN8
Fig. 18-UN8

47. You should now be able to:
Explain the concept of an operon and the function of the operator, repressor, and corepressor
Explain the adaptive advantage of grouping bacterial genes into an operon
Explain how repressible and inducible operons differ and how those differences reflect differences in the pathways they control

48. Explain how DNA methylation and histone acetylation affect chromatin structure and the regulation of transcription
Define control elements and explain how they influence transcription
Explain the role of promoters, enhancers, activators, and repressors in transcription control

49. Explain how eukaryotic genes can be coordinately expressed
Describe the roles played by small RNAs on gene expression
Explain why determination precedes differentiation
Describe two sources of information that instruct a cell to express genes at the appropriate time

50. Explain how maternal effect genes affect polarity and development in Drosophila embryos
Explain how mutations in tumor-suppressor genes can contribute to cancer
Describe the effects of mutations to the p53 and ras genes