Inhibition of cell growth and apoptosis by inducible expression of the transcriptional repressor Mad1.
Mad1 is a Myc antagonist that heterodimerizes with Max and functions as a transcriptional repressor. We have studied the effects of Mad1 on cell growth, cell cycle distribution, and apoptosis using Mad1-inducible cell lines. Expression of Mad1 inhibited cell proliferation, S-phase entry, and colony formation, changes that were accompanied by a reduction in CDK2 activity. The inhibition of Mad1 on cell proliferation was potentiated by serum starvation and was paralleled by accumulation of cells in the G0/G1 and the G2 phases of the cell cycle. Mad1 also reduced apoptosis induced by serum withdrawal and by the cytostatic drug cisplatinum. The effects on both cell growth and apoptosis were dependent on the mSin3 interaction domain of Mad1, which is necessary for recruitment of histone deacetylases and corepressors, suggesting that transcriptional repression is mediating these functions. Taken together with the expression pattern of Mad1, these results suggest that Mad1 plays an important role during initiation of differentiation by inhibiting cell proliferation and blocking apoptosis.
Bejarano
M T
MT
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, S-171 77, Sweden.
Albihn
A
A
Cornvik
T
T
Brijker
S O
SO
Asker
C
C
Osorio
L M
LM
Henriksson
M
M
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes / Q000235:genetics; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; C501384:MAD1L1 protein, human; C501385:Mad1l1 protein, mouse; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D010750:Phosphoproteins; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D002945:Cisplatin