Topics• Concept 8.5: Regulation of enzymes: What is an allosteric regulator? What

are some examples? How do they benefit an organism

• Concept 12.1: What is the relationship between a chromosome and DNA? Why do cells divide? Why do chromosomes replicate?

• Concept 12.3: How is the cell cycle regulated? Why is the cell cycle regulated?

• Concept 18.1: How do bacteria (prokaryotes) use operons to regulate the expression of genes? What is the benefit of controlling gene expression to a bacteria?

• Concept 18.2: How do eukaryotes (like us) control gene expression? Know transcription factors, RNA processing

• Figure 18.18: Why don’t all cells end up the same, especially given that they have the same genetic code?

• Figure 18.23: How can mistakes in the control mechanisms of gene expression lead to cancer? Relate this figure to the BCR-ABL transcription factor translocation that results in Chronic Myeloid Leukemia.

• Negative and Positive Feedback

Essential Knowledge

• 2.e.2: • 2.e.3• 3.b.1: • 3.b.2:• 4.c.2

Warm-UP: Check out this cool root tip! 1. How do you think the cells

compare in different parts of the root?

2. What might regulate the cells ability to be different in different places?

DUE Tomorrow: Lab Handout: Comparing Mitosis

UNIT 7/8 TEST: This Thursday (see website for Test Review)Inheritance and Regulation

DUE NOW: Stamp Sheet

Unit 8: Regulation

• Big Idea: Many biological processes involved in growth, reproduction, and homeostasis are dependent on regulation.

• Model: Chronic Myeloid Leukemia (CML), a type of blood cancer. Normally, the cell cycle is regulated so that cell death (apoptosis) and cell growth (mitosis) are balanced. In cancer, mutations affect gene expression by dys-regulating transcription factors, which in turn lead to changes in enzyme regulation of the cell cycle and subsequent tumor growth.

The cell cycle is regulated so that cell death (apoptosis) and cell growth (mitosis) are balanced.

Cell cycle• Mitotic (M) phase: mitosis and cytokinesis• Interphase accounts for 90% of the cell cycle

• G1: growth• S: DNA Replication (making sister chromatids)• G2: growth

• Checkpoints: Finish M phase?– The Go Signal! Regulatory Proteins

• transcription factor (TF): Cyclin• enzyme that regulates the TF: Cyclin-Dependent

Kinase (Cdk)Stop and Enter G0: Leaving the cell cycle

– G0: • protein that gets built: MPF (maturation-promoting

factor)• cell differentiation: one cell becomes different than

another because different genes are expressed• Maturation: cell expresses traits depending on

what type of cell it is

The cell cycle is regulated so that cell death (apoptosis) and cell growth (mitosis) are balanced.

Cell cycle• Mitotic (M) phase: mitosis and cytokinesis• Interphase accounts for 90% of the cell cycle

• G1: growth• S: DNA Replication (making sister chromatids)• G2: growth

• Checkpoints: Finish M phase?– The Go Signal! Regulatory Proteins

• transcription factor (TF): Cyclin• enzyme that regulates the TF: Cyclin-Dependent

Kinase (Cdk)Stop and Enter G0: Leaving the cell cycle

– G0: • protein that gets built: MPF (maturation-promoting

factor)• cell differentiation: one cell becomes different than

another because different genes are expressed• Maturation: cell expresses traits depending on

what type of cell it is

SG1

M checkpoint

G2M

Controlsystem

G1 checkpoint

G2 checkpoint

The cell cycle is regulated so that cell death (apoptosis) and cell growth (mitosis) are balanced.

Cell cycle• Mitotic (M) phase: mitosis and cytokinesis• Interphase accounts for 90% of the cell cycle

• G1: growth• S: DNA Replication (making sister chromatids)• G2: growth

• Checkpoints: Finish M phase?– The Go Signal! Regulatory Proteins

• transcription factor (TF): Cyclin• enzyme that regulates the TF: Cyclin-Dependent

Kinase (Cdk)Stop and Enter G0: Leaving the cell cycle

– G0: • protein that gets built: MPF (maturation-promoting

factor)• cell differentiation: one cell becomes different than

another because different genes are expressed• Maturation: cell expresses traits depending on

what type of cell it is

The cell cycle is regulated so that cell death (apoptosis) and cell growth (mitosis) are balanced.

Cell cycle• Mitotic (M) phase: mitosis and cytokinesis• Interphase accounts for 90% of the cell cycle

• G1: growth• S: DNA Replication (making sister chromatids)• G2: growth

• Checkpoints: Finish M phase?– The Go Signal! Regulatory Proteins

• transcription factor (TF): Cyclin• enzyme that regulates the TF: Cyclin-Dependent

Kinase (Cdk)Stop and Enter G0: Leaving the cell cycle

– G0: • protein that gets built: MPF (maturation-promoting

factor)• cell differentiation: one cell becomes different than

another because different genes are expressed• Maturation: cell expresses traits depending on

what type of cell it is

1. Focus on one field of view “in the middle” of the root cap

2. Focus at 400X3. Count ALL cells in interphase.

Count ALL cells in mitosis.4. Calculate % difference5. Change field of view, but stay

“just behind” the root cap. Repeat steps #2-4

6. Repeat #1-5, but move to the “end” (notice, there is a “cap” in front of the end)

Lab: Cell Division Regulation in Onion Roots

“cap”

Warm-UP: What is cancer? Why is cancer so hard to cure? What treatments do you know of?

DUE NOW: Lab Handout: Comparing Mitosis in Onion Cells

UNIT 7/8 TEST: This Thursday (see website for Test Review)Inheritance and Regulation

The cell cycle is regulated so that cell death (apoptosis) and cell growth (mitosis) are balanced.

Cell cycle• Mitotic (M) phase: mitosis and cytokinesis• Interphase accounts for 90% of the cell cycle

• G1: growth• S: DNA Replication (making sister chromatids)• G2: growth

• Checkpoints: Finish M phase?– The Go Signal! Regulatory Proteins

• transcription factor (TF): Cyclin• enzyme that regulates the TF: Cyclin-Dependent

Kinase (Cdk)Stop and Enter G0: Leaving the cell cycle

– G0: • protein that gets built: MPF (maturation-promoting

factor)• cell differentiation: one cell becomes different than

another because different genes are expressed• Maturation: cell expresses traits depending on

what type of cell it is

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cancer: dys-regulation of TFs of cell growth= more growth than death.• Transcription Factors: (TFs)

• cell-type specific TFs: proteins that bind to DNA and start transcription

• can be regulated: turned on (activated) or off (inhibited) by enzymes binding to “allosteric site”

Example: Chronic Myeloid Leukemia (CML)• Normal: Regulation of Myeloid Cell Maturation

– ABL gene ABL enzyme active TF for myeloid cell maturation to WBC

• Cancer: Dysregulation: myeloid cells do not enter G0, but instead stay in the cell cycle– driven by a chromosomal translocation (Translocation of

Chr22 onto end of Chr9 creating fusion gene of BCR and ABL (a kinase)

– BCR-ABL gene BCR-ABL enzyme active TF for myeloid cell division

– Result: leukemia• overproliferation of undifferentiated, immature cells• Anemic – low RBCs (chokes out growth of other blood

cells)• Low WBCs – prone to infection

Warm-UP: Predict a solution for CML. Remember competitive inhibitors for enzymes? (think flipping pennies with a tennis ball taped to your hand)

UNIT 7/8 TEST: Tomorrow (see website for Test Review)Inheritance and Regulation

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Cure: Gleevac• Drug that competitively inhibits

Bcr-Abl enzyme by filling the substrate site so TF for cell division gene cannot be activated

• First Targeted therapy for cancer

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Brian Druker and NovartisLate 1990s

Cure: Gleevac• Drug that competitively inhibits

Bcr-Abl enzyme by filling the substrate site so TF for cell division gene cannot be activated

• First Targeted therapy for cancer

In cancer, mutations affect gene expression by dys-regulating transcription factors which regulate enzymes.

Homeostasis could not be maintained if a cell’s metabolic pathways were not tightly regulated

Enzyme Regulators: switching on/off enzymes– bind to another part of an enzyme (the

allosteric site), – cause an enzyme to change shape and

changing the active site– can inhibit or activate– Example: Cell Cycle Regulation by cyclin,

an allosteric activator– Example: Dys-Regulation of Cell

Maturation by BCR-ABLCure: Gleevac• Drug that competitively inhibits Bcr-Abl

enzyme by filling the substrate site so TF for cell division gene cannot be activated

• First Targeted therapy for cancer