Transcription Factors

Slide 1 · Transcription Factors

MYC-mediated transcriptional programs and oncogenic growth

Mechanisms • molecular pathology • clinicopathologic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Lecture objectives

Explain how mitogenic signals converge on nuclear transcription factors.

Describe MYC regulation and the major MYC-dependent growth programs.

Distinguish MYC translocation, amplification and pathway-mediated activation.

Interpret cancer examples without confusing a molecular mechanism with a diagnostic test.

Slide 3 · A nuclear endpoint for mitogenic signaling

Growth factors activate signaling cascades that ultimately change gene expression.

Transcription factors translate signal activation into a nuclear growth program.

Continuous signaling can persistently activate growth-promoting genes.

Growth signal

Signal transduction

Nuclear transcription

Growth gene expression

Slide 4 · Transcription factors connect signals to phenotype

A pathway becomes biologically consequential when target-gene transcription changes.

The resulting proteins can control growth, division, survival and biosynthesis.

Transcription factors form the functional link between upstream signaling and output.

Pathway activity

Transcription factor

Target genes

Cellular behavior

Slide 5 · Oncogenic change: Upstream versus nuclear

Upstream activation

Receptor or signaling component is deregulated.

A normal transcription factor may receive persistent input.

Nuclear activation

A transcription-factor gene itself can be altered.

The output program becomes excessive despite physiologic control.

Slide 6 · A transcription factor can drive many target genes

Some factors coordinate a narrow transcriptional program.

Others regulate numerous genes with multiple functional consequences.

MYC is emphasized because its effects are especially broad.

Transcription factor

Cell-cycle genes

Ribosomal program

Metabolic genes

Other targets

Slide 7 · Transcription factors implicated in oncogenesis

The supplied cancer chapter lists MYC, MYB, JUN, FOS and REL as proto-oncogenes.

These genes encode transcriptional regulators of growth-associated programs.

MYC is the most frequently dysregulated member highlighted in this section.

MYC

MYB

JUN

FOS

REL

Slide 8 · Why the lecture centers on MYC

MYC is expressed in virtually all eukaryotic cells.

Its abundance is rapidly modulated following mitogenic stimulation.

Deregulated MYC is common across cancer types and alters multiple growth programs.

MYC

Cell cycle

Biosynthesis

Metabolism

Replicative capacity

Slide 9 · Transcription factors have modular functions

DNA-binding regions recognize short regulatory sequences.

Protein-interaction regions help recruit transcriptional machinery.

Regulatory modifications can change localization, activity and turnover.

DNA recognition

Protein interactions

Transcriptional machinery

Slide 10 · Specific DNA binding provides target selection

Transcription factors bind regulatory DNA motifs rather than all genomic sequences.

Motifs can lie near promoters or in distant enhancers.

The combination of DNA sites and co-regulators determines transcriptional output.

Schematic: Regulatory DNA

Regulatory motif

Promoter

Target gene

Regulatory relationships, not physical distances

Slide 11 · Promoters and transcription initiation

Promoters lie near the site where transcription begins.

Bound factors and associated proteins help recruit RNA polymerase.

Changes in promoter activity can increase target-gene RNA output.

Schematic: Regulatory DNA

Promoter

Transcription start

RNA product

Regulatory relationships, not physical distances

Slide 12 · Enhancers regulate genes at a distance

An enhancer can be far from its target promoter in the linear DNA sequence.

Chromatin looping places enhancer-associated factors near promoter machinery.

Enhancer activity can depend strongly on cell lineage.

Distant positions along DNA

Enhancer

Promoter

Promoter–enhancer communication

Gene

Slide 13 · Chromatin context shapes the response

A signal need not activate the same genes in every cell type.

Lineage-specific enhancer contacts can change the transcriptional response.

Therefore MYC activation mechanisms depend partly on cellular context.

Same input

Lineage A targets

Lineage B targets

Slide 14 · Co-regulators help transcription factors act

Protein interactions recruit coactivators and chromatin-modifying proteins.

Chromatin remodeling can expose transcription-initiation sites.

RNA polymerase catalyzes synthesis of the resulting RNA.

TF–DNA binding

Co-regulator recruitment

Chromatin accessibility

RNA synthesis

Slide 15 · Signal-dependent transcription-factor control

Posttranslational modifications can change nuclear localization.

They may expose DNA-binding regions or promote protein interactions.

They can also increase or decrease protein stability.

Regulatory signal

Localization

DNA binding

Interactions

Half-life

Slide 16 · MYC is an immediate-early response gene

Growth factor stimulation of quiescent cells activates RAS/MAPK signaling.

MYC transcription responds rapidly to this input.

The normal response is transient, not persistently maximal.

Growth factor

RAS/MAPK activation

Rapid MYC induction

Transient response

Slide 17 · The normal MYC response is a controlled pulse

Quiescent cells initially have low mitogen-induced MYC activity.

Growth stimulation produces rapid MYC upregulation.

Normal control limits the duration and abundance of MYC protein.

Quiescence

Mitogen exposure

MYC induction

Return toward baseline

Slide 18 · MYC abundance is regulated at three levels

Transcription determines production of MYC RNA.

Translation determines synthesis of MYC protein.

Protein stability determines how long that protein remains available.

Distinct regulatory layers

Transcription

Translation

Protein stability

Slide 19 · Cancer converts a transient program into persistence

Inappropriate mitogenic signaling can maintain MYC activity.

Direct oncogenic alterations may deregulate MYC independently.

Persistent MYC can drive continuing expression of progrowth genes.

Oncogenic alteration

Sustained MYC abundance

Growth gene program

Proliferation advantage

Slide 20 · MYC has pleiotropic transcriptional effects

MYC regulates gene expression programs with distinct cellular functions.

Its consequences extend beyond cell-cycle entry.

Many effects can cooperate within the same neoplastic cell.

MYC

Cell-cycle entry

Ribosome assembly

Metabolic supply

Other hallmarks

Slide 21 · MYC promotes cell-cycle progression

The MYC target-gene repertoire includes D cyclins.

D cyclins participate directly in progression through the cell cycle.

MYC therefore connects mitogenic signals with the cell-division machinery.

MYC activity

D-cyclin expression

Cell-cycle progression

Slide 22 · Division requires both regulatory and material inputs

Cell-cycle regulation licenses progression through division.

New cells also need proteins, lipids and nucleic acids.

MYC contributes to both the regulatory and biosynthetic arms of growth.

MYC

Cell-cycle control

Macromolecule synthesis

Cell growth

Cell division

Slide 23 · MYC increases ribosomal RNA production

MYC upregulates transcription of ribosomal RNA genes.

Ribosomal RNA is an essential structural and functional ribosome component.

More rRNA supports the expansion of protein-synthesis capacity.

MYC

RRNA gene expression

Ribosomal RNA supply

Ribosome production

Slide 24 · MYC also supports ribosomal RNA processing

Newly transcribed rRNA must be processed before functional ribosomes assemble.

MYC upregulates rRNA-processing processes as well as rRNA transcription.

The combined effect facilitates ribosome assembly.

RRNA transcription

RRNA processing

Ribosome assembly

Slide 25 · Ribosome biogenesis enables protein synthesis

An expanding cell must synthesize structural and regulatory proteins.

Ribosome assembly increases the capacity for translation.

MYC-supported ribosome biogenesis links gene regulation to cell growth.

MYC target program

More ribosomes

Greater protein synthesis capacity

Cell biomass

Slide 26 · MYC upregulates glycolytic components

MYC increases the expression of multiple glycolytic enzymes.

This is part of a wider metabolic gene-expression program.

The source associates this shift with the Warburg effect.

MYC activation

Glycolytic gene program

Metabolic reprogramming

Slide 27 · Metabolic reprogramming supports anabolic growth

Altered carbon metabolism supplies intermediates for biosynthesis.

The Warburg effect is discussed by Robbins as a cancer hallmark.

The biological purpose is not limited to producing cellular energy.

Metabolic rewiring

Biosynthetic intermediates

Macromolecule assembly

Slide 28 · MYC also affects glutamine metabolism

MYC regulates factors involved in glutamine utilization.

Glutamine-related pathways contribute biosynthetic intermediates.

This program cooperates with altered glycolysis to sustain growth.

MYC

Glutamine metabolism genes

Metabolic intermediates

Biosynthetic support

Slide 29 · Building blocks are needed for daughter cells

DNA synthesis requires nucleic-acid precursors.

Proteins require amino acids and biosynthetic capacity.

Cell membranes require lipid synthesis during growth.

Anabolic intermediates

DNA

Proteins

Lipids

Slide 30 · MYC coordinates metabolism and ribosome output

Glycolysis and glutamine programs supply intermediates.

Ribosome biogenesis provides capacity to translate proteins.

Cell-cycle drivers determine whether division machinery proceeds.

MYC

Metabolic supply

Ribosomal capacity

Cyclin expression

Cell proliferation

Slide 31 · In some contexts, MYC increases telomerase

The textbook specifically qualifies this effect as context-dependent.

Telomerase is one contributor to replicative immortality.

MYC regulation of telomerase is not presented as a universal cancer mechanism.

MYC in some settings

Telomerase expression

Replicative capacity

Slide 32 · MYC participates in somatic-cell reprogramming

MYC is among transcription factors that can act together in reprogramming.

Reprogramming can produce pluripotent stem-cell states.

The observation raises questions about similar programs in cancers.

Somatic cell

Multiple reprogramming factors

Pluripotent state

Slide 33 · MYC and cancer stemness: A hypothesis

A suspected contribution of MYC to cancer-cell stemness.

This hypothesis follows from MYC participation in somatic-cell reprogramming.

A possible relationship is not proof that all MYC-high tumors contain stemlike cells.

Observed role

Reprogramming with other TFs

Proposed role

Cancer-cell stemness

Slide 34 · MYC links several cancer hallmarks

Persistent expression promotes deregulated cell growth.

Metabolic programs support the anabolic phenotype.

Telomerase and reprogramming links suggest additional context-specific effects.

MYC dysregulation

Growth promotion

Metabolism

Immortality link

Stemness hypothesis

Slide 35 · Four broad routes to increased MYC output

Translocation can relocate MYC near a highly active enhancer.

Amplification can increase copies of a MYC-family gene.

Oncogenic upstream signaling can raise MYC protein levels.

Inherited variants in nearby enhancers may alter responsiveness.

Excess MYC

Translocation

Amplification

Signaling

Enhancer variation

Slide 36 · MYC translocation changes regulatory context

A chromosomal rearrangement can reposition a normally regulated gene.

The new locus can contain strong lineage-active enhancers.

The rearranged gene is then abnormally expressed.

Chromosomal rearrangement

New enhancer proximity

Deregulated MYC expression

Slide 37 · Antigen-receptor enhancers are highly active

B- and T-lymphocyte receptor loci contain strong regulatory elements.

In some lymphoid tumors, MYC moves into this enhancer-rich context.

Antigen-receptor regulatory activity is redirected toward MYC.

Normal regulatory neighborhood

Antigen-receptor enhancer

Native target locus

After regulatory juxtaposition

Antigen-receptor enhancer

Rearranged MYC

High MYC RNA

Slide 38 · Enhancer hijacking is a cis-regulatory mechanism

The active enhancer and MYC gene become juxtaposed by rearrangement.

The enhancer stimulates excessive MYC transcription.

Consequences follow from an altered DNA regulatory neighborhood.

Schematic: Regulatory DNA

Active enhancer

MYC promoter

MYC gene

Regulatory relationships, not physical distances

Slide 39 · Burkitt lymphoma: Canonical MYC deregulation

Burkitt lymphoma virtually always has a chromosomal translocation involving MYC.

A common rearrangement juxtaposes MYC with an immunoglobulin locus.

The associated enhancer drives unusually high MYC abundance.

Normal regulatory neighborhood

IG enhancer

Native target locus

After regulatory juxtaposition

IG enhancer

MYC rearrangement

MYC overexpression

Slide 40 · Why Burkitt lymphoma can grow so rapidly

The source links very high MYC abundance with very fast tumor growth.

The enlarged transcriptional program promotes biosynthesis and cell-cycle progression.

This is a mechanistic explanation, not a quantified doubling-time estimate.

Enhancer-driven MYC

Anabolic + cycle programs

Rapid neoplastic growth

Slide 41 · MYC translocations occur beyond Burkitt lymphoma

The textbook mentions subsets of other B-cell neoplasms.

It also describes MYC translocations in certain T-cell neoplasms.

Molecular context must therefore be interpreted with the tumor phenotype.

MYC translocation

B-cell context or T-cell context

Altered MYC expression

Slide 42 · Gene amplification is a second genetic route

Amplification increases the number of gene copies in a neoplastic genome.

Amplification of MYC can result in MYC overexpression.

This differs mechanistically from enhancer relocation.

MYC copy-number gain

Higher gene dosage

MYC overexpression

Slide 43 · MYC amplification spans several solid tumors

Robbins gives breast, colon and lung cancers as examples.

Other tissues may also contain MYC-amplified tumors.

These examples show that MYC deregulation is not confined to lymphoid tumors.

Breast

Colon

Lung

Other tissues

Slide 44 · MYC-family paralogs extend the mechanism

NMYC and LMYC as functionally identical related genes.

Amplification can affect these MYC-family genes.

Their cancer associations differ from MYC itself.

MYC

NMYC

LMYC

Slide 45 · NMYC amplification in neuroblastoma

Neuroblastoma is the canonical example given for NMYC amplification.

The lesion increases a MYC-family growth-regulatory program.

This example illustrates lineage-associated oncogene selection.

NMYC amplification

MYC-family overexpression

Neoplastic growth advantage

Slide 46 · LMYC amplification in small-cell lung cancer

LMYC amplification with small-cell lung cancers.

The altered gene belongs to the same functionally related family.

The mechanistic category is copy-number–driven transcription-factor activity.

LMYC amplification

MYC-family overexpression

Neoplastic growth advantage

Slide 47 · Translocation and amplification are not synonyms

Translocation

Rearranges chromosomal position.

Can place MYC beside a strong enhancer.

Amplification

Increases gene copy number.

Can elevate expression via increased dosage.

Slide 48 · MYC elevation need not involve MYC DNA itself

Cancer-associated pathway alterations can increase MYC transcription.

They can also enhance translation or prolong protein stability.

The result is excessive MYC even without a direct MYC rearrangement.

Upstream driver mutation

Altered MYC control

Increased MYC protein

Growth program

Slide 49 · RAS/MAPK signaling raises MYC expression

Physiologic RAS/MAPK activity can transiently induce MYC.

Constitutive pathway signaling can maintain MYC abundance.

The source notes this relationship in many different cancers.

RAS/MAPK activation

MYC induction

Progrowth transcription

Slide 50 · Notch signaling can converge on MYC

Aberrant Notch signaling is another cited route to MYC activation.

Robbins gives several cancers as the clinical setting.

The transcriptional consequences vary with cellular context.

Oncogenic Notch signal

MYC upregulation

Growth promotion

Slide 51 · Wnt signaling provides a colon-cancer example

The source lists Wnt-pathway activation in colon carcinoma.

One consequence is MYC upregulation.

MYC is an output effector, not necessarily the initiating pathway lesion.

Deregulated Wnt

MYC elevation

Growth-associated genes

Slide 52 · Hedgehog signaling links to MYC in medulloblastoma

Hedgehog-pathway dysregulation is listed in medulloblastoma.

This pathway can promote transformation partly through MYC upregulation.

The importance of this route depends on tumor context.

Deregulated Hedgehog

MYC upregulation

Growth promotion

Slide 53 · Pathways converging on MYC

Upstream pathway

Cancer context

Shared downstream theme

RAS/MAPK

Many cancers

Increased MYC abundance

Notch

Several cancers

MYC upregulation

Wnt

Colon carcinoma

MYC upregulation

Hedgehog

Medulloblastoma

MYC upregulation

Slide 54 · MYC overexpression can arise at different stages

Increased transcription generates more MYC RNA.

Enhanced translation yields more MYC protein from available RNA.

Protein stabilization extends the time MYC remains available.

Distinct regulatory layers

More MYC transcription

Greater MYC translation

Reduced protein turnover

Slide 55 · Noncoding variants can affect MYC regulation

Cancer-risk–associated SNPs may lie in enhancers near MYC.

Such variants can increase responsiveness to growth-promoting signals.

Regulatory DNA can therefore influence cancer susceptibility without coding change.

Alternative inherited regulatory alleles

Reference enhancer

Risk-associated enhancer SNP

Comparison of enhancer states

Signal-sensitive expression

Schematic: Altered responsiveness, not rearrangement

Slide 56 · Inherited MYC-enhancer variants: Interpretation

Examples cited include risk for prostate and ovarian cancer and certain leukemias.

The textbook says these enhancer variants appear to raise MYC RNA responsiveness.

No per-allele effect sizes or clinical prediction values are provided.

Inherited enhancer variant

Altered response to signals

Changed cancer susceptibility

Slide 57 · Mechanistic classification of MYC upregulation

Alteration

Immediate effect

Representative context

MYC translocation

Enhancer-driven expression

Burkitt lymphoma

MYC amplification

Increased gene dosage

Breast / colon / lung

NMYC or LMYC amplification

MYC-family copy gain

Neuroblastoma / small-cell lung

Upstream pathway activation

Altered transcription/translation/stability

RAS, Notch, Wnt, Hedgehog

Enhancer-risk SNP

Altered regulatory responsiveness

Inherited cancer susceptibility

Slide 58 · Case discussion: Rapidly growing B-cell tumor

A lymphoid tumor is found to carry a rearrangement involving MYC and an immunoglobulin regulatory region.

Reasoning questions

What mechanism increases MYC expression?

Why can this promote rapid tumor growth?

Enhancer hijacking places MYC under potent lymphoid regulatory activity; MYC stimulates cycle and biosynthetic programs.

Slide 59 · Case discussion: Wnt-active colon carcinoma

A colon carcinoma shows evidence of persistent Wnt signaling without an identified MYC rearrangement.

Reasoning questions

Can MYC still be elevated?

Where is the likely driver in the causal chain?

Yes. Upstream Wnt-pathway dysregulation can raise MYC as a downstream transcriptional effector.

Slide 60 · Case discussion: MYC-family copy-number gain

A neuroblastoma specimen is reported to contain amplification of NMYC.

Reasoning questions

Which oncogenic mechanism is illustrated?

Why is this different from an MYC translocation?

Copy-number amplification of a MYC-family gene, rather than relocation beside a potent enhancer.

Slide 61 · Interpretation pitfalls in molecular pathology

High MYC expression does not identify a unique molecular cause.

MYC rearrangement is not a standalone diagnosis without tumor context.

The excerpt does not justify numeric biomarker thresholds or sensitivity claims.

Stemness and telomerase effects must retain the qualifiers used by Robbins.

Molecular lesion

Gene-regulatory effect

Cellular phenotype

Clinicopathologic interpretation

Slide 62 · Integrated model of oncogenic MYC activation

A direct MYC lesion or an altered pathway elevates MYC output.

MYC coordinates cell-cycle, ribosomal and metabolic gene programs.

The combined program supports neoplastic expansion.

Excess MYC

Cell-cycle regulation

Ribosome biogenesis

Metabolism

Cell growth / division

Slide 63 · Synthesis: Six defensible conclusions

Mitogenic pathways converge on nuclear gene regulation.

MYC normally rises rapidly and transiently after growth stimulation.

MYC drives cell-cycle, ribosomal and metabolic growth programs.

Rearrangement, amplification and upstream signaling can raise MYC.

Some MYC effects are context-dependent or still inferential.

A molecular mechanism is not by itself a diagnostic classification.

Slide 64 · Textbook references

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed., Chapter 7: Neoplasia; Transcription Factors and MYC.

Same textbook, Chapter 1: Transcription Factors; DNA-binding domains, promoters, enhancers and co-regulators.