MOL BIOL 4H03 - AP-1 Transcription Factor

8/11/2019 MOL BIOL 4H03 - AP-1 Transcription Factor

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Leucine Zipper and Basic Region Binding to DNA


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Structure of the Jun Family Members

L L L LBTADDN C

Sites of phosphorylation (regulatory)

Docking Site (!domain in c-Jun, Menin domain in JunD)

Trans-Activation Domain (TAD)

Basic region (DNA binding)

Leucine Zipper (Dimerization domain)


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L L L LBTADD

DNA B. TAD

P P P

L L L LBTADD

P P

+ Stimulus (stress, oncogene, etc)

Control of c-Jun activity by phosphorylation/dephosphorylation

- Phosphorylation near the basic region is mediated mainly by

CKII and GSK3!while phosphorylation in the activation domain

depends on SAPK/JNK

- Phosphorylation potentiates the activity of the acidic c-JUN TAD

- SAPK/JNK interacts with c-Jun through a specific docking domain


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Two Waves of AP-1 induction

a) First: Post-translational regulation of Jun proteins

b)

Second: Transcriptional induction of c-Fos mRNA


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Evidence that AP-1 plays a role in oncogenesis

1- Both c-Jun and c-Fos have viral counterparts that are

oncogenic

2- AP-1 activity is elevated in cells transformed by RTK

and NRTK

3- The expression of a dominant negative mutant of c-Jun

(designated TAM67) blocks transformation by v-Src and

activated Ha-Ras

L L L LB

CL L L LBTADDN

CTAM67


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Regulation of AP-1 by dimerization Partners

- In several studies, JunB and JunD were shown to be

less potent than c-Jun in transactivation

-Over-expression of JunB and JunD inhibits

transformation by activated Ha-Ras in vitro

- Therefore, displacing a strong trans-activator such as

c-Jun or c-Fos may reduce the activity of AP-1


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Is JunB a Tumor Suppressor?

- Recent studies indicate that the absence of JunB in the

myeloid lineage promotes the development of myeloid

leukemia in the mouse

- Conditional inactivation of JunB in the epidermis of c-

Jun (+/-) mice promotes the formation of papillomas

- Therefore, JunB functions as a Tumor Suppressor at

least in some tissues.


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Regulation by dockingpartners: c-Jun vs JunD

L L L LBTADD

SAPK

P P

c-Jun

ACTIVATION


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Histone Acetylation Promotes Transcription Initiation

Co-Activators have HAT activityand recruit the basic transcription

machiney


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Histone Acetyl Transferases (HATs) promote chromatin relaxation

and the transcriptional activation

Histone DeACetylases (HDAC) promote chromatin condensation

and gene repression


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Why is c-Jun more potent than JunD?

L L L LBTADD

SAPK

P P

c-Jun

Menin

HDAC

JunD

ACTIVATION

REPRESSION


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JunD is negatively regulatedby the Menin Tumor Suppressor

- JunD does not contain a docking site for SAPK/JNK.

-

In JunD, the!

domain is replaced by a docking site forthe Menin Tumor Suppressor

- Menin is the product of the Multiple Endocrine

Neoplasia type I gene (Men1)

-

Men1 is a Tumor Suppressor gene causing multipletumors of the endocrine system (pancreas, parathyroids.

Etc) when deleted


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- Men1 (+/-) mice are also prone to developing multiple

endocrine neoplasia

-

Menin binds to the N-terminus of JunD and blockstranscriptional transactivation of JunD without affecting

DNA binding

- Menin interacts with histone deacetylase complexes

causing chromatin condensation and gene silencing

Regulation by dockingpartners

MOL BIOL 4H03 - AP-1 Transcription Factor

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