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c-Myc
The proto-oncogene, MYC, lies at the crossroads of many growth promoting signal transduction pathways and is an immediate early response gene downstream of many ligand-membrane receptor complexes. MYC expression is highly regulated, such that its level of expression is tightly control by a number of mechanisms involving many transcriptional regulatory motifs found within its proximal promoter region. Mammary carcinoma triggered by transgenic Myc expression acquired K-ras mutations that rendered tumors aggressive. Acute overexpression of MYC in normal cells triggers checkpoints including ARF or p53, such that many MYC-induced transgenic lymphomas lacks functional Arf or p53.
Among the vast numbers of targets that are repressed by Myc, a fraction is linked to Miz-1, which activates these genes. TGFβ signaling best illustrates a role for Myc-Miz-1 interaction. In the absence of TGFβ, Myc represses CDKN2B (p15INK4b) by binding Miz-1 and displacing Miz-1 cofactors to silence CDKN2B. With TGFβ, MYC expression is suppressed, and the Smad transcription factor translocates and cooperates with Miz-1 to recruit NPM1 as a Miz-1 cofactor to stimulate CDKN2B transcription and induce cell cycle arrest. Myc, on the other hand, activates many ribosomal protein genes including Rpl23, which binds to and retains NPM1 in the nucleolus, thereby inhibiting Miz-1 activity. Myc itself is modulated by NPM1, which acts as a positive Myc coactivator.
References
1.Chi V. Dang. Cell. 2012 Mar 30; 149(1): 22–35.
Among the vast numbers of targets that are repressed by Myc, a fraction is linked to Miz-1, which activates these genes. TGFβ signaling best illustrates a role for Myc-Miz-1 interaction. In the absence of TGFβ, Myc represses CDKN2B (p15INK4b) by binding Miz-1 and displacing Miz-1 cofactors to silence CDKN2B. With TGFβ, MYC expression is suppressed, and the Smad transcription factor translocates and cooperates with Miz-1 to recruit NPM1 as a Miz-1 cofactor to stimulate CDKN2B transcription and induce cell cycle arrest. Myc, on the other hand, activates many ribosomal protein genes including Rpl23, which binds to and retains NPM1 in the nucleolus, thereby inhibiting Miz-1 activity. Myc itself is modulated by NPM1, which acts as a positive Myc coactivator.
References
1.Chi V. Dang. Cell. 2012 Mar 30; 149(1): 22–35.
Cell Cycle/DNA Damage
ABC(7)
AChR(5)
Antifolate(8)
ATM/ATR(23)
Aurora Kinase(37)
CLK(15)
c-Myc(16)
DHFR(4)
DNA Alkylator(29)
DNA gyrase(7)
DNA Repair Protein(21)
DNA/RNA Synthesis(85)
DNA-PK(11)
GPR(19)
HDAC(111)
Hec1/Nek2(9)
Integrin(38)
LIM Kinase (LIMK)(4)
Mps1/TTK(1)
Nucleoside Antimetabolite/Analog(19)
Other Targets(2)
PARP(30)
PLK(11)
Potassium Channel(55)
RAD51(1)
Rho(5)
ROCK(13)
Telomerase(4)
Topoisomerase(40)
Wee1(2)