Презентация на тему Apoptosis and tumor suppressor proteins

mechanism characterized by nuclear condensation, cell shrinkage, membrane blebbing,

and DNA fragmentation.
Apoptosis, or programmed cell death, is an evolutionary conserved genetic process of cellular suicide, which plays a crucial role in sculpting the developing organism and in “pruning” billions of unwanted, unneeded, or damaged cells every day during adult life

Apoptosis can lead to Birth Defects
2) Important for maintaining

homeostasis
- Cell death is balanced with mitosis to regulate cell number.
3) Improper regulation contributes to human disease
- Neurodegenerative diseases
Parkinson’s
Alzheimer’s
-Cancer
- Autoimmune diseases e.g. (diabetes type I)
- Viral diseases

of cytochrome C
Nuclear condensation
Nuclear fragmentation
Cell membrane blebbing
Fragmentation; apoptotic body

formation: membrane-bound cellular fragments, which often lack nuclei
Phagocytosis

necrosis is not
Apoptosis is more rapid (12-24 hours) than

necrosis
Apoptosis is induced by endogenous or exogenous stimuli, necrosis is always induced by exogenous harms
Apoptosis is limited to single or few cells at a time, and occurs among healthy cell population, necrosis is usually more extensive & occurs in tissue exposed to injuries
Cell cytoplasm shrinks in apoptosis and swells in necrosis.
Nucleosomes of apoptotic cells are 180 bp fragments, contrary to the irregular ones in necrosis
Apoptosis has no inflammation, while necrosis leads to liberation of pro-inflammatory mediators
Apoptosis has no systemic manifestations contrary to most inflammations

i. Committment to death by extracellular or intracellular triggers/signals
ii.

Cell killing (execution) by activation of intracellular proteases (caspases)
iii. Engulfment of cell corpse by other cells
iv. Degradation of the cell corpse within the lysosomes of phagocytic cells

by binding to their specific receptor.
Typical examples of

death factors are:
Fasligand, FAS L
TNF (tumor necrosis factor) and
TRAIL (TNF-related apoptosis-inducing ligand).
- Apoptosis can also be induced by cytotoxic T-lymphocytes using the enzyme granzyme.

described above eventually activate the executioner (caspase) cascade
ii.

At least 14 different caspases exist in human cells
iii. Caspase cascades are apparently required for complete execution

changes in the inner mitochondrial membrane, resulting in the

mitochondrial permeability transition (MPT) and release of cytochrome c and other pro-apoptotic proteins into the cytosol, which activate caspases.
AIF= Apoptosis inhibitory factor;
IAPs= Inhibitors of apoptosis proteins;
Apaf-1= apoptosis protease activating factor

term caspases is derived from cysteine-dependent aspartate-specific proteases
The caspase

cascade can be activated by:
Granzyme B released by cytotoxic T lymphocytes which is known to activate caspase-3 and -7;
death receptors (like FAS, TRAIL receptors and TNF receptor) which can activate caspase-8 and -10; and
the apoptosome, regulated by cytochrome c and the Bcl-2 family, which activates caspase-9.

апоптоза относятся ростовые факторы. Другие: нейтральные аминокислоты, цинк, эстрогены,

андрогены, некоторые белки.
Пример: Белки семейства 1АР — подавляют активность каспаз 3 и 9, один из этих белков (Survin) обнаружен в опухолевых клетках. С ним связывают резистентность опухолевых клеток к химиотерапии.
Активаторы апоптоза(проапоптические факторы). Это проапоптические гены и их продукция: гены семейства BCL-2 (ВАХ и BID); гены Rb и Р53 (запускают апоптоз, если клетка задержана механизмом checkpoint).
Патогенез многих заболеваний, в том числе и опухолевых, связан со снижением способности клеток подвергаться апоптозу. Отсюда накопление поврежденных клеток и формирование опухоли.

recognized to play a role in tumorigenesis, and indeed,

Bcl-2 is overexpressed in a variety of cancers, contributing to cancer cell survival through direct inhibition of apoptosis.
BCL-2 is a human proto-oncogene located on chromosome 18.
Its product is an integral membrane protein (called Bcl-2) located in the membranes of the endoplasmic reticulum (ER), nuclear envelope, and in the outer membrane of the mitochondria.
The gene was discovered as the translocated locus in a B-cell leukemia (hence the name). This translocation is also found in some B-cell lymphomas.

Этот факт - стимул для активации генов-супрессоров.
2. Гены-супрессоры продуцируют

белки Rb и р53.
3.Белки Rb и р53 запускают апоптоз поврежденной клетки. Это - индукторы апоптоза. Белок р53 индуцирует апоптоз в момент G1/S. Белок Rb индуцирует апоптоз в момент G2/M.

клетку с поврежденной ДНК. Дефект гена-супрессора ведет к размножению

поврежденной клетки. Пролиферация поврежденной клетки - основа опухолевого роста.
Наследование генов-супрессоров. В каждой клетке есть по два аллеля любых генов. Значит, в каждой клетке есть два гена-супрессора. Дефект одного гена-супрессора повышает риск пропуска в митоз поврежденной клетки. Дефект обоих генов-супрессоров всегда приводит к пропуску в митоз поврежденной клетки и опухолевому росту.
Пример: наследственная ретинобластома - опухоль сетчатки глаза - диагностируется в раннем детском возрасте (зрачок отсвечивает красным). Этиология - наследственный дефект гена-супрессора Rb и как следствие - постоянный пропуск в митоз клеток с поврежденной ДНК.

Functions:
halts growth and division in cell cycle under

aberrant conditions
induces apoptosis
Loss of p53 function leading cause in 30-50% of various types of cancers

Повреждение ДНК
2. Активация гена р53 и продукция соответствующего белка
3.

Активация проапоптических генов семейства BCL-2 (ВАХ и BID)
4. Образование белков этих генов
5. Активация каспазы 9
6. Активация каспазы 3
7. Активация других каспаз и протеаз
8. Апоптоз

a tumor suppressor gene, i.e., its activity stops the

formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.
The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.

– Role of Mitochondria on apoptosis
https://www.youtube.com/watch?v=Rlk9ZzInzuA – Extrinsic Pathway/

TNF
https://www.youtube.com/watch?v=f8CpWl-Tqf8 – E/Fas ligand