Session 7 - Cellular Adaption Flashcards
Cyclins and CDKs (cyclin dependent kinase)
- what are cyclins?
- what is there role?
Cyclins:
Cyclinsare among the most important corecell cycle regulators.
Cyclins are a group of related proteins, and there are four basic types found in humans and most other eukaryotes: Cyclin D, Cyclin E, Cyclin A, Cyclin B
As the names suggest, each cyclin is associated with a particular phase, transition, or set of phases in the cell cycle and helps drive the events of that phase or period.
Cyclins promote the events. For instance, cyclin B promotes the events of M phase, such as nuclear envelope breakdown and chromosome condensation.
What are cyclin-dependent kinases?
Cyclin-dependent kinase:
In order to drive the cell cycle forward, a cyclin must activate or inactivate many target proteins inside of the cell. Cyclins drive the events of the cell cycle by partnering with a family of enzymes called the cyclin-dependent kinases (Cdks). A lone Cdk is inactive, but the binding of a cyclin activates it, making it a functional enzyme and allowing it to modify target proteins.
How does this work? Cdks are kinases, enzymes that phosphorylate (attach phosphate groups to) specific target proteins. The attached phosphate group acts like a switch, making the target protein more or less active. When a cyclin attaches to a Cdk, it has two important effects: it activates the Cdk as a kinase, but it also directs the Cdk to a specific set of target proteins, ones appropriate to the cell cycle period controlled by the cyclin.
- Retinoblastoma protein
- p53
-
Retinoblastoma protein:
The RB tumor suppressor protein limits cell proliferation by preventing entry into the S phase of the cell cycle. RB achieves its inhibitory effect by blocking the activity of E2F. -
p53
-> Checkpoints and regulators
Cdks and cyclins, are direct regulators of cell cycle transitions, but they aren’t always in the driver’s seat. Instead, they respond to cues from inside and outside the cell. p53 can be activated by many stressors e.g. hypoxia, DNA damage, oxidative stress, nutrient deprivation, oncogene expression. These cues influence activity of the core regulators to determine whether the cell moves forward in the cell cycle. Positive cues, like growth factors, typically increase activity of Cdks and cyclins, while negative ones, like DNA damage, typically decrease or block activity.
p53 is a tumour suppressor, it works on multiple levels to ensure that cells do not pass on their damaged DNA through cell division. First, it stops the cell cycle at the G1 checkpoint by triggering production of Cdk inhibitor (CKI) proteins. The CKI proteins bind to Cdk-cyclin complexes and block their activity (see diagram below), buying time for DNA repair. p53’s second job is to activate DNA repair enzymes. If DNA damage is not fixable, p53 will play its third and final role: triggering programmed cell death so damaged DNA is not passed on.
By ensuring that cells don’t divide when their DNA is damaged, p53 prevents mutations (changes in DNA) from being passed on to daughter cells. When p53 is defective or missing, mutations can accumulate quickly, potentially leading to cancer. Indeed, out of all the entire human genome, p53 is the single gene most often mutated in cancers. p53 and cell cycle regulation are key topics of study for researchers working on new treatments for cancer
Cell population size - changes to cell population size due to…
• Rate of cell proliferation • Rate of cell differentiation • Rate of cell death by apoptosis
Increased numbers = increase proliferation and/or decrease cell death
Cell proliferation can be - physiological or pathological
Excessive physiological stimulation can become pathoogical e.g. benign prostatic hypertrophy
How can cells adapt?
- list a few
- make a mindmap to show the relationship between them
- Hyperplasia – cells increase in number above normal
- Hypertrophy – cells increase in size
- Atrophy – cells become smaller
- Metaplasia – cells are replaced by cells of a different type
Hyperplasia:
- Define
- Type of tissue
- Why does this occur
- One risk
- Physiological hyperplasia examples
- Pathological hyperplasia
- Define hyperplasia: Increase in tissue or organ size due to increased cell numbers
- Type of tissue: Labiel or stable tissues
- Why does this occur: Increased functional demand or external (hormonal) stimukation, remains under physiological cause but the proliferation itself is a normal response
- One risk: Repeated cell divisions exposes the cell to the risk of mutations and neoplasia (risk of mutations - increase risk of neoplasia)
- Physiological hyperplasia examples:
- — Proliferative endometrium under influence of oestrogen
- — Bone marrow produce erythrocytes in response to hypoxia
- Pathological hyperplasia
- — Eczema
- Thyroid goitre in iodine deficiency
Hypertrophy
- Define
- Type of tissue
- What causes hypertrophy
- Physiological hypertrophy
- Define: Increase in tissue or organ size due to increased cell size
- Type of tissue: Labile, stable but especially permanent tissues
- What causes hypertrophy?
• Increased functional demand or hormonal stimulation
• Cells contain more structural components – workload is shared by a greater mass of cellular components
• In labile and stable tissues hypertrophy usually occurs along with hyperplasia
- Physiological hypertrophy: Skeletal muscle, pregnant uterus
- Pathological hypertrophy
Compensatory hypertrophy
Kidney’s in development, can:
- not form
- one can be very small
- formed but tissues within are ‘hap-hazard’, aren’t formed properly
…one kidney is removed, the other enlarges
Atrophy
- Define
- Explain, does this lead to cell death?
- Organ/tissue atrophy is typically due to a combination of…
- Physiological atrophy
- Pathological atrophy
- Define: Shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells
-
Explain:
• Shrinkage in the size of the cell to a size at which survival is still possible • Reduced structural components of the cell • May eventually result in cell death -
Organ/tissue atrophy is typically due to a combination of:
• Organ/tissue atrophy typically due to combination of: Cellular atrophy and Apoptosis • Is reversible but only up to a point
Physiological atrophy: (see pic) Ovarian atrophy in post menopausal women
Pathological atrophy:
• Reduced functional demand/workload = atrophy of disuse: muscle atrophy after disuse, reversible with activity e.g. plaster cast.
• Loss of innervation = denervation atrophy: wasted hand muscles after median nerve damage
• Inadequate blood supply: thinning of skin on legs with peripheral vascular disease (atherosclerosis and arteriosclerosis of the arteries)
• Inadequate nutrition: wasting of muscles with malnutrition
• Loss of endocrine stimuli: breast (pregnancy increases breast tissue – and then removal of hormone leads to atrophy, reproductive organs
• Persistent injury: polymyositis (inflammation of muscle)
• Aging = senile atrophy: brain, heart
• Pressure: tissues around an enlarging benign tumour (probably secondary to ischaemia)
Metaplasia
- Define
- Tissue types
- Reason for metaplasia
- Reversible?
- Potential problems associated
- One key thing about the d______
- Define: Reversible change of one differentiated cell type to another. Adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment. Altered stem cell differentiation
- *- Tissue types:** Labile or stable cell types
- *- Reason for metaplasia:** Adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment.
- *- Metaplastic cells are fully differentiated and the process is reversible** (link into dysplasia and cancer lectures)
- *- Potential problems associated:** Can lead to dysplasia and cancer (if stimulus not removed)
– No metaplasia across germ layers (endoderm/endoderm not ectoderm/mesoderm)
Examples of metaplasia
- 2 examples
- Bronchioles:
Bronchial pseudostratified ciliated epithelium -> stratified squamous epithelium due to effect of cigarette smoke - Barrett’s oesophagus
Stratified squamous epithelium -> gastric glandular epithelium with persistent acid reflux (Barrett’s oesophagus)
Spleen undergoes metaplasia to bone marrow, so it can still produce blood cells
Does metaplasia predispose to cancer?
- Yes
• Epithelial metaplasia can lead to dysplasia and cancer.
• Smokers: Squamous metaplasia and lung squamous cell carcinoma
• Oesophagus - reflux: Barrett’s epithelium and oesophageal adenocarcinoma
• Stomach: Intestinal metaplasia of the stomach and gastric adenocarcinoma
Aplasia
Aplasia –
the complete failure of a specific tissue or organ to develop. It is an embryonic developmental disorder, e.g., thymic aplasia which results in infections and auto-immune problems, aplasia of a kidney. The term aplasia is also used to describe an organ whose cells have ceased to proliferate, e.g., aplasia of the bone marrow in aplastic anaemia.
Hypoplasia
- define
- example
- opposite of hyperplasia?
Hypoplasia - the congenital underdevelopment or incomplete development of a tissue or organ. There are an inadequate number of cells within the tissue which is present. It is an embryonic developmental disorder and is in a spectrum with aplasia,
e.g., renal hypoplasia, breast hypoplasia, testicular hypoplasia in Klinefelter’s syndrome, hypoplasia of the chambers of the heart.
It is not the opposite of hyperplasia as it is a congenital condition. Compare it with atrophy which occurs when an existing part wastes away.
Involution
- Define
- Example
Involution – a term which overlaps with atrophy. It is the normal programmed shrinkage of an organ, e.g., uterus after childbirth, thymus in early life, temporary foetal organs such as the pro- and mesonephros
Reconstitution
- Define
- Example
Reconstitution - this is different to regeneration in that it is the replacement of a lost part of the body rather than a small group of cells.
It requires the coordinated regeneration of several types of cells. Examples include the regrowth of a lizard’s tail and the growth of deer antlers (which can grow at 17.5mm/day). In mammals, many cell types can regenerate well but the ability to reconstitute a body part is minimal. Most mammals can’t even reconstitute a lost nail bed or the root of a hair (note that scars are hairless).
Atresia
- Explain
- Example
Atresia – ‘no orifice’, the congenital imperforation of an opening,
e.g., atresia of the anus or vagina
Dyplasia
Dysplasia – the abnormal maturation of cells within a tissue. It is potentially reversible but is often a pre-cancerous condition (this will be described in the sessions you have on neoplasia)
