cell cycle,growth regulation,molecular basis of cancer

1. DR.TASNIM ARA JHILKY
MD part II
Phase_ A
Biochemistry department
Sir Solimullah Medical College,Midford Dhaka

2. CELL CYCLE
 .

3. Cell cycle
M
Mitosis
G1
Gap 1
G0
Resting
G2
Gap 2
S
Synthesis
 Cell has a “life cycle”
cell is formed from
a mitotic division
cell grows & matures
to divide again
cell grows & matures
to never divide again
G1, S, G2, M G1G0
epithelial cells,
blood cells,
stem cells
liver cells
brain / nerve cells
muscle cells

4. Cell cycle phases
 G1 phase-growth and synthesis (hrs to yrs)
 S phase- DNA synthesis phase(7 hrs)
 G2 phase-Preparation for division(upto 5 hrs)
 M phase-M phase includes the overlapping processes of
mitosis and cytokinesis(1 to 2 hrs)
 Combination of G1,S,G2 phage is known as interphage
 90% of cell life cycle
 cell doing its “everyday job”
 produce RNA, synthesize proteins/enzymes
 prepares for duplication if triggered

5. Phases of cell cycle……

6. Representation of mitosis stages

7. Check Point
 .

8. Checkpoint

10. G1-S checkpoint…..

11. G2 checkpoint….

12. M checkpoint….

13. Importance of checkpoint

14. Regulation of cell cycle
 Cell cycle regulation is necessary for healthy growth

15. Regulation of cell cycle
Internal and external factors regulate cell division.
 External factors include physical and chemical signals.
 Growth factors are proteins that stimulate cell
division.

16.  Two of the most important internal factors are kinases and
cyclins.
 Cyclin: group of proteins that triggers action of kinases.it is so
named because of the cyclic nature of their production and
degradation.more than 15 cyclin identified.cyclin D,E,A,B
appear sequentially during cell cycle.
 Kinase: enzymes that affect molecule’s activity
 Together these both help a cell advance to different stages of
the cell cycle.the cyclin cdk complex phosphorylates crucial
target proteins that drive the cell through cell cycle .on
completion cyclin levels decline rapidly.
• External factors trigger internal factors,
which affect the cell cycle.
External
growth
factors
Cyclins
Kinases
Triggered cell
cycle
activities

17. Regulation of
cell cycle:
The orderly
progression of
cells through the
various phases of
cell cycle is
arranged by
cyclins and cyclin-
dependent kinases
(CDKs), and
by their inhibitors.

19. Fundamental principles of
carcinogenesis:
 Nonlethal genetic damage lies at the heart of carcinogenesis-Such
genetic damage (or mutation) may be acquired by the action of
environmental agents, such as chemicals, radiation, or viruses, or it
may be inherited in the germ line.
 tumors are monoclonal: A tumor is formed by the clonal expansion of
a single precursor cell that has acquired genetic damage.

20. Principal Targets of Genetic Damage:
4 Classes of Normal Regulatory Genes
 Growth-promoting proto-oncogenes
 Growth-inhibiting tumor suppressor genes
Apoptosis-regulating genes; genes that regulate the
programmed cell death
 DNA repair genes

21. Carcinogenesis is a multistep process resulting from the accumulation of
multiple mutations at phenotypic and genotypic levels.
these mutations accumulate independently in different clonal cells,
generating subclones with varying abilities to grow, invade, metastasize,
and resist (or respond to) therapy.
Over a period of time tumors not only increase in size but become more
aggressive and acquire greater malignant potential (tumor progression)

23. Essential alterations for malignant
transformation
 1. Self-sufficiency in growth signals: Tumors have the capacity to
proliferate without external stimuli, usually as a consequence of
oncogene activation.
 2. Insensitivity to growth-inhibitory signals : Tumors may not respond
to molecules that are inhibitory to the proliferation of normal cells
such as transforming growth factor β (TGF-β) and direct inhibitors of
cyclin-dependent kinases (CDKIs).

24. Cont…………
 .3. Evasion of apoptosis: Tumors may be resistant to programmed cell
death, as a consequence of inactivation of p53 or activation of anti-
apoptotic genes.
4. Limitless replicative potential: Tumor cells have unrestricted
proliferative capacity, avoiding cellular senescence and mitotic
catastrophe.

25. •5. Sustained angiogenesis: Tumor cells, like normal cells, are not able
to grow without formation of a vascular supply to bring nutrients and
oxygen and remove waste products. Hence, tumors must induce
angiogenesis.
•6. Ability to invade and metastasize : Tumor metastases are the cause of
the vast majority of cancer deaths and depend on processes that are
intrinsic to the cell or are initiated by signals from the tissue
environment.

26. Con………..
 .
•7. Defects in DNA repair : Tumors may fail to repair DNA damage
caused by carcinogens or incurred during unregulated cellular
proliferation, leading to genomic instability and mutations in proto-
oncogenes and tumor suppressor genes.
Another important change for tumor development is escape from
immune attack .

27. Self-sufficiency in growth signals
(Oncogenes)
 Genes that promote autonomous cell growth in cancer cells ,are called
oncogenes.
 Their unmutated cellular counterpart are called proto-oncogene.
 Oncogenes are created by mutations in proto-oncogene and are
characterized by the ability to promote cell growth in the absence of
normal groth promoting signals .
 Their products called onco proteins ,resemble the normal product of
proto-oncogenes except that onco protein are devoid of any signal for
growth.
 In this way they become autonomus.

28. Normal cell Proliferation
The binding of a growth factor to its specific receptor
Transient and limited activation of the growth factor receptor
Activates several signal-transducing proteins on the inner leaflet of the
plasma membrane
Transmission of the transduced signal across the cytosol to the nucleus
via second messengers or by a cascade of signal transduction molecules
Induction and activation of nuclear regulatory factors that initiate DNA
transcription
Entry and progression of the cell into the cell cycle, ultimately resulting
in cell division

29. Proto-oncogene,oncogene
 .
In a normal cell, Proto-oncogenes have multiple roles, participating in
cellular functions related to growth and proliferation.
Self sufficiency for growth to a cancerous cell is provided by oncogenes,
which are the mutant proto-oncogenes.
Mutations convert inducible proto-oncogenes into constitutively active
oncogenes, which is responsible for progressive cell divisions.

31. Oncogenes
Growth factors
Growth factor
receptors
Signal
transduction
proteins
Nuclear
regulatory
proteins
Cell cycle
regulators

32. Growth Factors
 Normally cell require stimulation by GFs to undergo
proliferation.
 Mostly these GFs are secreted by one cell type and act on a
neighboring cell to stimulate proliferation. (paracrine action)
 Cancer cells acquire the ability to synthesize their own GFs
generating an autocrine loop.
 Examples: - Glioblastomas secrete PDGF
- Sarcomas secrete TGF-α

33. Growth Factor Receptors
 Several oncogenes that encode growth factor receptors have been
found.
Ex. Transmembrane proteins with an external ligand-binding domain and
a cytoplasmic tyrosine kinase domain.
 In the normal forms of these receptors, the kinase is transiently
activated.
 The oncogenic versions of these receptors, kinase is constitutively
activated. Resulting in continuous mitogenic signals to the cell, even
in the absence of growth factor in the environment

34. Signal-Transducing Proteins
 signal-transducing proteins plays an important role in signaling
cascades downstream of growth factor receptors, resulting in
mitogenesis.
 RAS is a signal transducing oncoprotein belonging to family of GTP-
binding proteins (G proteins). Point mutation of RAS family genes
(HRAS, KRAS, NRAS) is the single most common abnormality of
proto-oncogenes in human tumors.
KRAS- colon and pancreas
HRAS- bladder tumors
NRAS- hematopoietic tumors.
 Approximately 15% to 20% of all human tumors contain mutated
versions of RAS proteins.

36. Alteration in nonrecptor kinases
 In CML and some acute lymphoblastic leukemias, the ABL
gene is translocated from its normal habitat on chromosome
9 to chromosome 22. The resultant chimeric gene encodes a
constitutively active, oncogenic BCR-ABL tyrosine kinase.

37. Nuclear Regulatory Proteins
(Transcription Factors)
 all signal transduction pathways converge to the nucleus where
stimulation of nuclear transcription factors allow them for DNA
binding. Binding of these proteins to specific sequences in the genomic
DNA activates transcription of genes.
 Growth autonomy may thus occur as a consequence of mutations
affecting genes that regulate transcription.

38. Cell Cycle Regulators
(Cyclins and Cyclin-Dependent Kinases)
The ultimate outcome of all growth-promoting stimuli is the entry of
quiescent cells into the cell cycle. Cancers may grow autonomously if the
genes that drive the cell cycle become dysregulated by mutations or
amplification.

39. Example of cell cycle regulator genes and associated cancers:
• Overexpression of cyclin D genes - cancer of breast, esophagus, liver,
and a subset of lymphomas.
• Amplification of the CDK4 gene - melanomas, sarcomas, and
glioblastomas.
While cyclins arouse the CDKs, their inhibitors (CDKIs) silence the
CDKs and exert negative control over the cell cycle. The CDKIs are
frequently mutated or otherwise silenced in many human malignancies.
• Germline mutations of p16 - melanoma.
• Somatically acquired deletion or inactivation of p16 - pancreatic
carcinomas, glioblastomas, esophageal cancers, acute lymphoblastic
leukemias, non-small-cell lung carcinomas, soft-tissue sarcomas, and
bladder cancers.

42. .
 RB protein, the product of the RB gene, is a ubiquitously
expressed nuclear phosphoprotein that plays a key role in
regulating the cell cycle.
 germline loss or mutations of the RB gene -
retinoblastomas and osteosarcomas.
 Somatically acquired RB mutations - glioblastomas,
small-cell carcinomas of lung, breast cancers, and bladder
carcinomas.

43. Insensitivity to Growth-Inhibitory Signals
(Tumor Suppressor Gene)
 Failure of growth inhibition is one of the fundamental alterations in
the process of carcinogenesis. Whereas oncogenes drive the
proliferation of cells, the products of tumor suppressor genes apply
brakes to cell proliferation.
 It has become apparent that the tumor suppressor proteins form a
network of checkpoint that prevent uncontrolled growth..
 There are so many tumor suppressor includesTGF-B,NF1,NF2,RB1
P53 ,BRCA1,BRCA2.

44. • The p53 gene is located on chromosome 17p13.1, and it is the most
common target for genetic alteration in human tumors.
• p53 acts as a “molecular policeman” that prevents the propagation of
genetically damaged cells.
• P53 inhibits neoplastic transformation by three interlocking
mechanisms: activation of temporary cell cycle arrest (quiescence),
induction of permanent cell cycle arrest (senescence), or triggering of
programmed cell death (apoptosis).
• Homozygous loss of p53 occurs in virtually every type of cancer,
including carcinomas of the lung, colon, and breast—the three leading
causes of cancer death.

45. Role of p53 in Maintaining the
Integrity of Genome

46. Limitless Replicative
Potential
most normal human cells have a capacity of 60 to 70 doublings. After
this, the cells lose their ability to divide and become senescent. This
phenomenon has been ascribed to progressive shortening of telomeres
at the ends of chromosomes.

47. Defects in DNA repair
 Although humans literally swim in environmental agents that are
mutagenic (e.g., chemicals, radiation, sunlight), cancers are relatively
rare outcomes of these encounters. This state of affairs results from the
ability of normal cells to repair DNA damage and the death of cells
with unrepairable damage.
 Defects in three types of DNA-repair systems contribute to different
types of cancers
 mismatch repair,
nucleotide excision repair, and
recombination repair

48. Chemical Carcinogenesis

49. Viral Carcinogenesis
 Human papilloma virus (HPV)
 Epstein-Barr virus (EBV)
 Hepatitis B virus (HBV)
 Human T-cell leukemia virus type 1(HTLV-1)
These viruses have the potential to induce the carcinogenesis,
by causing the mutation of various genes regulating normal
cellular function

51. cancer ribbon