Lecture 8

Question 1

TGFb prevents phosphorylation of

Answer 1

Rb-blocks cell cycle progression

Question 2

TGFb prevents phosphorylation of Rb-blocks cell cycle progression

Answer 2

• Major Growth inhibitory signal forNormal Cells
• Counteracts actions of MYC (MYC is growth promoting).
  – MYC represses expression of both p15 and p21.
• In normal cells TGFb reduces c-MYC expression-Smad3 and E2F4/5 and
  p107 shut down c-MYC expression. In breast cancer this TGFb-mediated
  repression of MYC is LOST.
• TGFb signalling-Smad2/3 associate with Smad4-heterotrimeric complex
  moves to nucleus-collaborates with Miz-1 (TF) to induce expression of p21
  and p15 (CDKIs). In cancers where MYC is overexpressed these CDKIs are
  repressed (oncogenic MYC wins over TGFb signals).
• Many cancers evade TGFb growth inhibition (eg half of pancreatic cancers
  have mutant inactivated Smad4 proteins)

Question 3

Other Controls
Damaged DNA…role of p53.

Answer 3

Another feedback mechanism prevents division in the
presence of damaged DNA (halt at G1, G2, or M)
p53 protein involved
p53 gene mutation is common in many transformed
cells.

Question 4

Akt

Answer 4

• Akt, a serine/threonine kinase is activated downstream of Growth factor Receptors
• Functions include inhibition of CDK Inhibitors and promoting progression of cell
  cycle by blocking the actions of GSK3b. (GLYCOGEN SYNTHASE KINASE 3b)
• Also blocks the actions of a pro-apoptotic protein, Bad, (later lecture on Apoptosis)
  and promotes cell growth

Question 5

Growth Factors (eg EGF) that signal through Akt lead to the

Answer 5

inhibition
of the actions of the CDKIs p21 and p27. (A) Akt phosphorylates p21 and
p27, which leads to their translocation from the nucleus to the
cytoplasm-degraded by proteosome

Question 6

Akt also phosphorylates

Answer 6

GSK3b leading to the inactivation of GSK3btargets of GSK3b include MYC and CyclinD1 (GSK3b inhibitory action on
both MYC and CyclinD1)

Question 7

In cancer

Answer 7

“Hallmark” features of Cancer is Autonomous cell
division (ie no longer dependent on positive and
negative growth factors)
* The PI3K-AKT and RAS-RAF-MEK-ERK pathways are
thought to play a central role in transmitting oncogenic
signals.
* So Is the expression levels altered or the activity altered
(eg if a kinase for example) of proteins such as Akt, RAS
or MYC in Cancer-are they different from normal cells?
* Yes Eg in BREAST CANCER=
* RAS and Akt are abnormally activated and MYC
amplification is a frequent event in breast tumors

Question 8

Increased Akt Activity is a frequent event in

Answer 8

Cancer including Breast cancer

Question 9

TUMOR GRADE LINKED WITH HIGHER

Answer 9

pAKT EXPRESSION
AND REDUCED NUCLEAR P27