Lecture 8 Flashcards

1
Q

TGFb prevents phosphorylation of

A

Rb-blocks cell cycle progression

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2
Q

TGFb prevents phosphorylation of Rb-blocks cell cycle progression

A
  • 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)
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3
Q

Other Controls
Damaged DNA…role of p53.

A

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.

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4
Q

Akt

A
  • 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
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5
Q

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

A

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

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6
Q

Akt also phosphorylates

A

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

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7
Q

In cancer

A

“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

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8
Q

Increased Akt Activity is a frequent event in

A

Cancer including Breast cancer

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9
Q

TUMOR GRADE LINKED WITH HIGHER

A

pAKT EXPRESSION
AND REDUCED NUCLEAR P27

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