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MCC > Wk 5 Hedgehog and Beta-Catenin Signaling > Flashcards

Wk 5 Hedgehog and Beta-Catenin Signaling Flashcards

1
Q

What is hedgehog, SHH?

A

-A cell fate pathway that helps to pattern tissues and organs during embyonic development
-Extracellular signals that drive gene expression to determine proliferation, survival and differentiation of cells

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2
Q

What is the most common invasive cancer in humans?

A

basal cell carcinoma
-SHH can give rise to it

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3
Q

Characteristics of basal cell carcinoma

A

slow growing, rarely metastatic (but it’s so common that still means lots of metastatic cases)
-usually in sun-exposed, lightly pigmented areas
-from UV-induced DNA damage
-arises from keratinocytes in the basal epidermis

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4
Q

3 Tx for basal cell carcinoma

A
  1. small isloated lesions removed by excision or cryosurgery
  2. larger lesions (or eyelids, nose, ears, etc) - Mohs surgery
  3. metastatic BCC treated w/ smoothened inhibitors or chemo
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5
Q

What does basal cell carcinoma look like?

A

Pearly papules w/ prominent dilated subepidermal blood vessels (telangiectasias)

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6
Q

What is Mohs surgery?

A

Iterative “remove, test, remove” process w/ surgeion, pathologist and sometimes reconstructive surgeon
-curative in >97% of cases

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7
Q

Wnt and SHH pathways

A
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8
Q

SHH pathway

A

Inhibits membrane protein, Patched, which inhibits another membrane protein, Smoothened, which inhibits PKA, which inhibits GLI, which activates gene expression

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8
Q

SHH pathway

A

Inhibits receptor membrane protein, Patched (PTCH1), which inhibits another membrane protein, Smoothened, which inhibits PKA, which inhibits GLI, which activates gene expression

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9
Q

What is GLI?

A

A DNA-binding protein/ transcription factor that promotes proliferation

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10
Q

How does PKA inhibit GLI?

A

phosphorylates 3 serines and 3 threonines

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11
Q

Which proteins in the HH pathway are promotors of proliferation?

A

Hh, SMO (smoothened), and GLI1

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12
Q

What proteins in the Hh pathway are tumor suppressors?

A

PTCH1 (and theoretically Sufu)

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13
Q

What activates Smoothened (SMO)?

A

cholesterol binding

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14
Q

What is Patch (Ptch)?

A

cholesterol transporter in the membrane
-prevents Smo from accessing cholesterol
- in development, Hh binds Ptch and inactivates it
- in cancer, it can get mutated, giving Smo access to cholesterol and therefore activating it

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15
Q

2 drugs that are smoothened (Smo) inhibitors

A
  1. Vismodegib
  2. Sonidegib

both are competitive inhibitors of cholesterol and bind to Smo, so Smo is turned off and oncogenic signaling is also turned off

16
Q

What is the common first mutation in colon cancer?

A

Loss of tumor suppressor APC (adenomatous polyposis coli).
-discovered in FAP (familial adenomatous polyposis) w/ loss of heterozygosity in colonic epithelium -> polyps

17
Q

How is intestinal crypt architecture driven?

A

By local gradients of signaling molecules
-stem cells at bottom of crypt differentiate, progress to top of crypt/finger-like projections where they’re sloughed off (5-10 days)
-process is under control of Wnt and beta-catenin signaling

18
Q

What are the steps of stem cell differentiation in the colon via Wnt?

A
  1. stem cell maintenance by Wnt. beta-catenin decides when the process of differentiation will occur
  2. SCs become transit amplifying cells that proliferate by ephrin gradient
  3. cells differentiate, controlled by TGFbeta, Hh. BMP, and others
  4. apoptosis
19
Q

Wnt pathway

A

Wnt is an extracellular signal that:
1. binds Frizzled and LRP on the membrane
2. bound Frizzled causes it to stop inhibiting GSK3-beta (a beta-catenin inhibitor)
3. activates beta-catenin
5. activates TCF (T-cell factor)
6. activates gene expression

20
Q

What is Wnt?

A

extracellular signal that initiates differentiation program and starts the timer on inducing apoptosis 5-10 days later
-one of the “cell fate” signals that drives decisions that determine proliferation, survival, and differentiation of cells

21
Q

What is APC?

A

in Wnt pathway, initiates growth and sets up cell’s death w/in short time frame
-major molecule for cancer mutation, tends to get point mutations or truncations that cause decreased fxn
-a tumor suppressor, so have to get rid of both copies for full effect
~80% of APC mutations are truncations
-mutations -> increased beta-catenin, which -> more cell proliferation

22
Q

What is the role of E-cadherins?

A

Senses when there is contact with neighbors. If cells lose contact, sensed by E-cadherin, which then stops inhibiting beta-catenin so that cell proliferation can occur.
Without neighbors, E-cadherin binds beta-catenin and sequesters it away from the nucleus.

23
Q

What does Wnt signaling do to beta-catenin?

A

Stabilizes (and therefore activates) beta-catenin

24
Q

What is beta-catenin?

A

-it is always being made and destroyed constitutively

25
Q

What is the beta-catenin destruction complex?

A

A large E2/E3 ubiquitin ligase complex

26
Q

What are the important molecules in the beta-catenin destruction complex?

A
  1. scaffolding protein APC, holds complex together
  2. 2 serine/threonine kinases: casein kinase I and GSK3-beta (modify beta-catenin and allow for recognition by E3)
  3. docking protein called axin (acts as a signalling molecule when Wnt binds to Frizzled and LRP, it gains affinity for them and tells others to fall apart - a recognition protein)
  4. E3 that recognizes the target. E3 is betaTrCP (beta transducin repeat-containing protein)
  5. proteosome attaches after beta-catenin gets unbiquitized and destroys it before it can get to the nucleus
27
Q

What is the cascade when Wnt is ON?

A

Wnt binds Frizzled and LRP forming a terinary complex that has affinity for axin and binds
-> causes beta-TrCP (the E3) to fall off the complex
-> E2 doesn’t have its E3, so beta-catenin goes to the nucleus
-> beta-catenin is a co-activator of transcription w/ TCF (T cell factor, a DNA-binding protein)

28
Q

What is Groucho?

A

A co-repressor that is bound to TCF constitutively to keep it from binding to DNA
-can be displaced by beta-catenin, a co-activator

29
Q

What does Wnt binding ultimately cause?

A

stabilization of beta-catenin to allow it to bind TCF and cause gene transcription for differentiation and proliferation

30
Q

What happens when APC is gone?

A

Will always have condition that looks like Wnt is on
-beta-catenin destruction complex cannot function w/o APC so beta-catenin stays on and isn’t destructed

31
Q

What are the most common APC mutations?

A

truncations by stop codons or frameshifts so end of gene isn’t made
-detectable w/ western blots
-since part is missing, doesn’t fxn in beta-catenin destruction complex

MCC (44 decks)

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