Name: egf signaling and cancer cell growth
Uploaded: 2021-04-07T12:12:01.000Z
Duration: 2 min 38 s
Channel: JoVE

K12 Standards

Next Generation Science Standards

High School

Life Science

from-molecules-to-organisms-structures-and-processes

From Molecules to Organisms: Structures and Processes

HS-LS1-4

Mitogens and the Cell Cycle

Unicellular organisms, such as bacteria, divide when there are enough nutrients in the environment.
However, in multicellular organisms, most cells remain in G0, or the non-dividing phase, until cell division is triggered by extracellular signal molecules, called &#39;mitogens&#8217;.
Mitogens are usually small proteins or peptides secreted in response to different stimuli, such as tissue injury, infection, or a routine regeneration.
For instance, in the case of tissue injury, specialized cells secrete a mitogen called Platelet-derived growth factor or PDGF.
Such mitogens can bind to the extracellular domain of tyrosine kinase receptors such as PDGF-Receptor, inducing receptor dimerization and autophosphorylation of its intracellular domains. This allows phosphorylation and activation of the downstream intracellular molecules that are involved in multiple signaling pathways.
The mitogen-activated protein kinase or MAP kinase cascades are a type of signaling pathway induced by mitogen-receptor binding. This pathway starts with the activation of the small membrane bound GTPase named Ras by the receptor.
Next, active Ras triggers the MAP kinase cascade which includes a series of kinase proteins. In a chain of phosphorylation reactions, first MAP3 kinase activates MAP2 kinase, and then finally MAP kinase.
Active MAPK then translocates into the nucleus where it activates regulatory transcription factors, including Myc.
Myc increases the expression of G1 cyclins that partner with cyclin-dependent kinases or Cdks.
The G1 cyclin-Cdk complex phosphorylate Rb - a tumor suppressor protein - freeing the bound gene regulatory factor-E2F. Active E2F then binds to a specific DNA sequence and triggers transcription of cell cycle genes that encode several proteins necessary for cell division.
As the mitogenic stimuli recede, such as during the healing of injured tissues, Rb protein interacts with E2F inhibiting its activity, thus, preventing excessive cell growth.

mitogens and the cell cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell&#39;s proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase receptors present on the cell membrane, it transmits a growth-inducing signal to the corresponding cells. However, overactivation of EGFR can lead to tumor growth, invasion, and metastasis. It needs to be inactivated in the cancer cells to induce cell cycle arrest, dedifferentiation, or programmed cell death. Hence, the development of novel and targeted cancer therapies requires a deeper understanding of the mechanism and coordination between the mitogen and the cell cycle.
Role of Epidermal Growth Factor (EGF) as a mitogen in cancer therapeutics
In non-malignant tissues, the number of EGFR on the cell surface is tightly regulated to ensure that the cell division rate accurately matches the tissue&#39;s requirement. However, in cancerous cells, EGFR is overexpressed and is often perpetually stimulated by EGF or EGF-like proteins secreted by the cancer cell itself. A similar effect may occur when a mutation in EGFR drives the receptor into a state of continual activation. Overexpression of EGFR and closely associated ErbB2 receptors are associated with more aggressive clinical behavior, such as in Grade 3 cancers where tumor cells can likely spread to other parts of the body. Therefore, therapies directed at inhibiting the function of overactive receptors in the cancer cells can be used as anti-cancer therapies.
Monoclonal antibodies (MAbs) that block activation of EGFR and ErbB2 have been developed. These MAbs have shown promising preclinical studies. For example, trastuzumab, an anti-ErbB2 MAb, was recently approved to treat patients with metastatic ErbB2-overexpressing breast cancer. Another MAb, IMC-C225, an anti-EGFR, has shown impressive activity to revert tumor cells&#39; resistance to chemotherapy.

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell ...

Education

JoVE Core

Molecular Biology

Unit 2

Cell Proliferation

KEY TERMS AND CONCEPTS

egf signaling and cancer cell growth

Epidermal growth factor, or EGF, is a mitogen that helps control cell division. Its receptor, EGFR, sits in the cell membrane and sends a growth signal when EGF binds to it. EGFR is part of the ErbB family of tyrosine kinase receptors, and this signaling helps decide whether a cell will keep proliferating.

In healthy tissue, the number of EGFR molecules on the cell surface is tightly regulated. This balance helps cell division match the tissue’s needs. In cancer cells, however, EGFR is often overexpressed and can stay active for too long. The receptor may also be driven into constant activation by mutation or by EGF-like proteins made by the cancer cell itself.

Too much EGFR activity can support tumor growth, invasion, and metastasis. It can also make cancer cells more aggressive, as seen in Grade 3 cancers where tumor cells are more likely to spread to other parts of the body. To stop this, EGFR must be inactivated so the cell can enter cell cycle arrest, dedifferentiate, or undergo programmed cell death.

This signaling pathway is important in cancer research because targeted therapies can block overactive receptors. Monoclonal antibodies, or MAbs, have been developed to prevent EGFR and ErbB2 activation. Trastuzumab, an anti-ErbB2 MAb, has been approved for metastatic breast cancer with ErbB2 overexpression, and IMC-C225, an anti-EGFR MAb, has shown strong activity in reversing tumor resistance to chemotherapy.

EGF Signaling and Cancer Cell Growth

what is the cell cycle?

Cell Growth and Division in the Cell Cycle

The cell cycle is the process that cells use to grow and divide. It helps living things make new cells for growth and repair. In many cases, it is also the way single cells reproduce. The cycle has two main parts: interphase and cell division. During interphase, the cell grows and prepares for division. During cell division, one cell splits into new cells. This sequence keeps cells in a repeating pattern of growth, copying, and splitting.

interphase

Interphase in the Cell Cycle

Interphase is the part of the cell cycle when a cell grows and prepares to divide. It is a major stage in the life of a cell, and it includes the phases G1, S, and G2. During G1, the cell grows and carries out its normal functions. In the S phase, the cell copies its DNA. During G2, the cell continues to grow and gets ready for mitosis, the stage when the cell divides. Interphase takes up most of the cell cycle. It gives the cell time to build materials, make a copy of its genetic...

the cell cycle control system

How Cell Division Is Controlled

The cell cycle is the organized process that controls cell division. It helps one cell divide into two daughter cells with chromosomes that match the parent cell. This process is essential for growth from a single-cell zygote and for tissue renewal in adult multicellular eukaryotes. Cell division also supports repair and replacement in the body. In bone marrow, stem cells divide to make new blood cells. When cell division happens without control, it can lead to cancer and many genetic diseases.

positive regulator molecules

Cyclins and Cdks in Cell Cycle Control

Cyclins and cyclin-dependent kinases help control how cells move through the cell cycle. These positive regulator molecules keep mitotic cell division on schedule so daughter cells can match the parent cell. When this control fails, errors in DNA replication or in the distribution of genetic material can create mutant cells that pass those changes to every new cell they form. Cell cycle checkpoints limit the spread of these abnormal cells. A checkpoint is a control point at a specific stage of...

inhibition of cdk activity

Cdk4/6 Blockers and Cell Cycle Control

Cdk4/6 blockers help control the cell cycle by stopping the signals that push cells from G1 into S phase. Cdks, or cyclin-dependent kinases, must bind cyclins to become active, and cyclin D often pairs with Cdk4/6 to form this active complex. The cyclin D-Cdk4/6 complex then phosphorylates the retinoblastoma protein, or Rb, which normally acts as a tumor suppressor. When Rb is inactivated, cells can move into the next stage of division. In normal cells, Cdk activity is carefully regulated so...

s-cdk initiates dna replication

Cdk Control of DNA Replication Timing

Cdk control of DNA replication timing helps cells copy DNA once each cycle. The cell cycle has four main stages: G1, S, G2, and M. In G1, the cell grows. In S phase, it copies its DNA. In G2, it prepares to divide. In M phase, mitosis divides the cell content into two daughter cells. In eukaryotes, DNA replication starts at many sites on the chromosomes called origins of replication. These origins switch between two states during the cell cycle. In G1, a multiprotein pre-replicative complex,...

m-cdk drives transition into mitosis

Cell Cycle Kinases Trigger Entry into Mitosis

Cell cycle kinases help control the move from G2 into M phase. Checkpoints act as safeguards and gatekeepers, so the cell cycle can continue in good conditions and slow down or stop when problems appear. This regulation is called the cell cycle control system. Cyclin-dependent kinases, or Cdks, work with cyclins to manage cell cycle transitions. A key example is M-Cdk, which is made of Cdk1 bound to M cyclin. M-Cdk helps drive the shift from G2 to M phase by preparing the cell for mitosis. M...

Epidermal growth factor, or EGF, is a mitogen that helps control cell division. Its receptor, EGFR, sits in the cell membrane and sends a growth signal when EGF binds to it. EGFR is part of the ErbB family of tyrosine kinase receptors, and this signaling helps decide whether a cell will keep proliferating. In healthy tissue, the number of EGFR molecules on the cell surface is tightly regulated. This balance helps cell division match the tissue’s needs. In cancer cells, however, EGFR is often...

replicative cell senescence

Telomeres, Telomerase, and Tumor Control

Telomeres and telomerase help control how many times a cell can divide. Telomeres are short, repetitive DNA sequences at the ends of chromosomes. They are covered by proteins that form a protective cap. In many human body cells, this cap gets a little shorter after each round of cell division. This shortening is part of replicative senescence, the point at which a cell stops dividing permanently. Embryonic stem cells make telomerase, an enzyme that adds telomeric repeats and supports repeated...

abnormal proliferation

Ras and MYC in Uncontrolled Cell Growth

Ras and MYC can drive abnormal cell proliferation, which is uncontrolled cell growth. Under normal conditions, most adult cells stay non-proliferative unless they receive internal or external signals to replace lost cells. In abnormal proliferation, cell division continues even after those signals stop. This persistent growth can lead to tumors. The tumor forms from damaged cells that keep copying themselves. Those cells pass the damage to daughter cells and to later generations of daughter...

cells coordinate growth and proliferation

cells-coordinate-growth-and-proliferation

Cell Size Control in Growth and Muscle

Cell size control helps cells keep their shape, function, and fitness. Many dividing cells grow and then double their mass before they divide. This coordination depends on checkpoints between cell cycle phases, which help the cell stay in balance. When checkpoint control fails, cells may grow without proper control. That loss of coordination can lead to uncontrolled growth and reduced cellular function. In adult tissues, non-dividing cells also adjust size based on metabolic state. Adult...

key terms and concepts

Learn how EGF binds EGFR to control cell division, why overactive receptors can drive tumors, and how monoclonal antibodies target cancer growth.

EGF Signaling and Cancer Cell Growth | JoVE K12

molecular biology

JoVE Core Molecular Biology showcases the molecular processes of the cell through clear and concise animated video lessons. Additionally, in scientist-in-action videos, these concepts' application is demonstrated through real experiments in modern laboratories.

Texas Essential Knowledge and Skills

Biology

BIO.6

BIO.6.A

Characteristics of Life

Biology is a natural science that studies life and living organisms, including their structure, function, development, interactions, evolution, ...

https://cloudfront.jove.com/files/media/science-education/science-education-thumbs/10647.jpg

Cell Structure

Background
Cells represent the most basic biological units of all organisms, whether it be simple, single-celled organisms like bacteria, or large, ...

Visualizing Onion and Cheek Cells
ExpandImmediately before the experiment, wash and peel onion bulbs for the class.
Remove the entire brown outer skin and ...

Visualizing Onion and Human Cells
ExpandIn this experiment you will prepare different types of cells from a plant and animal, onion and human ...

What are Cells?

Cell Diversity

The concept of a cell started with microscopic observations of dead cork tissue by Robert Hooke in 1665. Hooke coined the term &#34;cell&#34; based on the ...

Cytoplasm

The cytoplasm consists of organelles and a framework of protein scaffolds called the cytoskeleton suspended in an aqueous solution, the cytosol. The ...

The Nucleus

The nucleus is a membrane-bound organelle that acts as a control center in a eukaryotic cell. It contains chromosomal DNA, which controls gene expression ...

The Central Dogma

The DNA Helix

Nucleic Acids

DNA as a Genetic Template

Structure of a Gene

A gene is the fundamental unit of heredity. Every individual has two copies of each gene, one inherited from each parent. Although most people contain the ...

Chromosome Structure

Base-pairing and DNA Repair

What is Gene Expression?

A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is comprised&#160; of nucleotides and proteins are ...

RNA Structure

The basic structure of RNA consists of a string of ribonucleotides attached by phosphodiester bonds. Although most RNA is single-stranded, it can form ...

Protein Families

Types of RNA

Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse ...

Conservation of Protein Domains

Transcription

Transcription is the synthesis of RNA from a DNA sequence by RNA polymerase. It is the first step in producing a protein from a gene sequence. ...

Globular and Fibrous Proteins

Translation

Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes ...

Intrinsically Disordered Proteins

Ribosomes

Ribosomes translate genetic information encoded by messenger RNA (mRNA) into proteins. Both prokaryotic and eukaryotic cells have ribosomes. Cells that ...

Protein Complex Assembly

Protein and Protein Structures

Conjugated Proteins

Proteins: From Genes to Degradation

Amyloid Fibrils

What are Proteins?

Proteins are polymers of amino acids linked together by peptide bonds. Proteins and polypeptides are interchangeably used to refer to long chains of amino ...

Ligand Binding Sites

Protein Organization

Proteins are polymers of amino acid residues. They are versatile and responsible for different cellular functions, including DNA replication, molecular ...

Protein-Protein Interfaces

Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to ...

Conserved Binding Sites

Cofactors and Coenzymes

Enzymes are proteins made of amino acids. The functional group of each constituent amino acid catalyzes a wide variety of chemical reactions via ionic ...

Cooperative Allosteric Transitions

Protein Kinases and Phosphatases

GTPases and their Regulation

Covalently Linked Protein Regulators

protein-complexes-with-interchangeable-parts

Protein Complexes with Interchangeable Parts

Mechanical Protein Function

Structural Protein Function

Protein Networks

Construct an explanation based on evidence for how the structure of DNA determines the structure of proteins, which carry out the essential functions of life through systems of specialized cells. [Assessment Boundary: Assessment does not include identification of specific cell or tissue types, whole body systems, specific protein structures and functions, or the biochemistry of protein synthesis.]

HS-LS1-1

Levels of Organization

Biological organization is the classification of biological structures, ranging from atoms at the bottom of the hierarchy to the Earth&#x27;s biosphere. ...

Animal and Plant Cell Structure

Animal and plant cells not only differ in their structure, function, and mode of nutrition but also in how they reproduce, specialize, and organize into ...

structural-organization-of-the-human-body-an-overview

Structural Organization of the Human Body: An Overview

It is convenient to consider the body&#39;s structures in terms of fundamental levels of organization that increase in complexity: subatomic particles, ...

Overview of Human Digestion

The human body contains a monogastric digestive system. In a monogastric digestive system, the stomach only contains one chamber in which it digests food. ...

Anatomy of the Intestines

Although digestion of proteins, carbohydrates, and lipids may begin in the stomach, it is completed in the intestine. The absorption of nutrients, water, ...

Accessory Organs

Accessory organs are those that participate in the digestion of food but do not come into direct contact with it like the mouth, stomach, or intestine do. ...

Lipid Digestion

Lipids are large molecules that are generally not water-soluble. Since most of the digestive enzymes in the human body are water-based, there are specific ...

Protein Digestion

Protein digestion begins in the stomach, where the highly acidic environment can easily disrupt protein structure by exposing the peptide bonds of ...

Carbohydrate Digestion

Carbohydrate digestion and metabolism break down simple and complex carbohydrates from food into saccharides (i.e., sugars) for the body to use as energy. ...

What is a Nervous System?

Overview

The nervous system is the collection of specialized cells responsible for maintaining an organism&rsquo;s internal environment and coordinating ...

The Parasympathetic Nervous System

Overview

The parasympathetic nervous system is one of the two major divisions of the autonomic nervous system. This parasympathetic system is responsible ...

The Sympathetic Nervous System

Overview

The sympathetic nervous system&mdash;one of the two major divisions of the autonomic nervous system&mdash;is activated in times of stress. It ...

Oogenesis

In human women, oogenesis produces one mature egg cell or ovum for every precursor cell that enters meiosis. This process differs in two unique ways from ...

What is a Sensory System?

Sensory systems detect stimuli&mdash;such as light and sound waves&mdash;and transduce them into neural signals that can be interpreted by the nervous ...

Fertilization

During fertilization, an egg and sperm cell fuse to create a new diploid structure. In humans, the process occurs once the egg has been released from the ...

What is the Skeletal System?

Overview

The adult human skeleton comprises 206 bones that are connected through cartilage, tendons, and ligaments. The skeleton provides a rigid ...

an-introduction-to-the-zebrafish-danio-rerio

An Introduction to the Zebrafish: Danio rerio

Zebrafish (Danio rerio) are small freshwater fish that are used as model organisms for biomedical research. The many strengths of these fish include their ...

Physiology of the Circulatory System

Homeostasis
Conditions in the external environment of an organism can change rapidly and drastically. To survive, organisms must maintain a fairly ...

Anatomy of the Circulatory System

The human circulatory system consists of blood, blood vessels that carry blood away from the heart, around the body, and back to the heart, and the heart ...

Measuring Blood Pressure
ExpandTo prepare for the blood pressure exercise, simply place the appropriate number of alcohol swabs, sphygmomanometers, and ...

Anatomy of the Heart

The human heart is made up of three layers of tissue that are surrounded by the pericardium, a membrane that protects and confines the heart. The ...

Measuring Circulatory System Function in Humans
ExpandBefore starting the experiment go to the front of the room and collect an alcohol swab, a ...

Blood Flow

Blood is pumped by the heart into the aorta, the largest artery in the body, and then into increasingly smaller arteries, arterioles, and capillaries. The ...

What Are Osmoregulation and Excretion?

Organisms must keep bodily fluids at a constant temperature and pH while maintaining specific solute concentrations in order to support life functions. ...

Blood Withdrawal I

Source: Kay Stewart, RVT, RLATG, CMAR; Valerie A. Schroeder, RVT, RLATG. University of Notre Dame, IN
Blood collection is a common requirement for ...

Kidney Structure

The kidneys are two large bean-shaped organs located in the upper abdomen. They filter the blood several times a day to remove toxins and rebalance water ...

Blood Withdrawal II

Source: Kay Stewart, RVT, RLATG, CMAR; Valerie A. Schroeder, RVT, RLATG. University of Notre Dame, IN
The collection of blood from mice and rats for ...

What is the Immune System?

Overview

The immune system comprises diverse biological structures and processes that protect the body from disease. These processes can be classified ...

Bone Remodeling

Bone remodeling is a continuous and balanced process of bone resorption by osteoclasts and bone formation by osteoblasts. In adults, it helps maintain ...

Spermatogenesis

Spermatogenesis is the process by which haploid sperm cells are produced in the male testes. It starts with stem cells located close to the outer rim of ...

Bone Structure

Within the skeletal system, the structure of a bone, or osseous tissue, can be exemplified in a long bone, like the femur, where there are two types of ...

Breathing

The process of breathing, inhaling and exhaling, involves the coordinated movement of the chest wall, the lungs, and the muscles that move them. Two ...

Develop and use a model to illustrate the hierarchical organization of interacting systems that provide specific functions within multicellular organisms. [Clarification Statement: Emphasis is on functions at the organism system level such as nutrient uptake, water delivery, and organism movement in response to neural stimuli. An example of an interacting system could be an artery depending on the proper function of elastic tissue and smooth muscle to regulate and deliver the proper amount of blood within the circulatory system.] [Assessment Boundary: Assessment does not include interactions and functions at the molecular or chemical reaction level.]

HS-LS1-2

What is Homeostasis?

Maintaining homeostasis requires that the body continuously maintain its internal conditions. Each physiological condition has a particular set point, ...

Negative and Positive Feedback

Homeostatic Imbalance

Homeostasis is the maintenance of a stable internal environment within the body, which is crucial for the proper functioning of cells, tissues, organs, ...

pH Homeostasis

Acid-base homeostasis is essential for maintaining normal physiological activities in humans. The pH of various body fluids is strictly regulated because ...

Positive and Negative Feedback Loops

Animal organs and organ systems constantly adjust to internal and external changes through a process called homeostasis (&#34;steady state&#34;). Examples ...

Plan and conduct an investigation to provide evidence that feedback mechanisms maintain homeostasis. [Clarification Statement: Examples of investigations could include heart rate response to exercise, stomate response to moisture and temperature, and root development in response to water levels.] [Assessment Boundary: Assessment does not include the cellular processes involved in the feedback mechanism.]

HS-LS1-3

EGF Signaling and Cancer Cell Growth

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