Cell cycle,growth regulation ,molecular basis of cancer by dr.Tasnim
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The document discusses cell cycle regulation and carcinogenesis. It can be summarized as follows: 1. The cell cycle is regulated by cyclins and cyclin-dependent kinases (CDKs), which help cells advance through different stages. External growth factors and internal factors like cyclins and kinases control progression. 2. Carcinogenesis is a multistep process caused by accumulating genetic mutations that alter genes regulating cell growth, apoptosis, and DNA repair. These mutations activate oncogenes and inactivate tumor suppressor genes. 3. For malignant transformation, tumors acquire self-sufficiency in growth signals, insensitivity to growth inhibitors, evasion of apoptosis, limitless replication, angiogenesis, invasion and metastasis
Cell cycle,growth regulation ,molecular basis of cancer by dr.Tasnim
- 1. DR.TASNIM ARA JHILKY MD part II Phase_ A Biochemistry department Sir Solimullah Medical College,Midford Dhaka
- 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 G1G0 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
- 8. Checkpoint
- 11. G2 checkpoint….
- 12. M 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
- 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