these mutations can be directly induced by specific cancer - causing agents such as radiations , chemicals , hormones , viruses and genetic factors 2 . after transformation , the cancer cells lose their ability to control cell division , but still maintain certain characteristics of the cells from which they are derived . tumor suppressors prevent cancer by reliably controlling cell division , promoting apoptosis , and suppressing metastasis 3 . once a tumor suppressor becomes inactive , cell division may proceed out of control and this may lead to cancer . tumor suppressors affect both the initiation and the development of cancer , and generally follow the classic  two - hit  model 3 - 5 . if one allele becomes mutated ( heterozygosis ) or underexpressed , the other can still express the appropriate tumor suppressor to inhibit cell division 5 . when both alleles are mutated or underexpressed , the inhibition of cell division is reduced and even lost 5 . the production of p27 from the unmutated allele is not sufficient enough to bring the cell to its original condition in the heterozygote , and the cell mitosis can only be arrested when both alleles are unmutated 6 . many tumor suppressors have activity in both normal and tumor cells ; whereas the others , such as p53 , are inactive in normal cells and only activated by potential cancer risks for example , the most important tumor suppressor p53 , which is associated with about 50% of human cancer cases 7 , can trigger dna repair processes , induce the transcription of other tumor suppressors , such as p21 and p16 , and initiate cell apoptosis 3 , 8 , 9 . despite the tremendous growth in cancer research and identification of numerous tumor suppressors 10 , the exact underlying mechanisms through which the tumor suppressors function are not always clearly revealed . to date , four major mechanisms have been revealed for tumor suppressors : suppression of cell division , induction of apoptosis , dna damage repair and inhibition of metastasis . the tumor suppressors that adopt this mechanism include retinoblastoma protein ( rb ) , adenomatosis polyposis coli ( apc ) , alternate reading frame ( arf ) , riz1 , p15 , p16 , p18 , p19 , p21 , p27 , and p53 8 , 9 , 11 - 21 . rb , which is the first discovered tumor suppressor , inhibits the transcription of specific genes required for mitosis through binding to transcription factors such as e2fs , which are key cell proliferation regulators 12 , 13 . tumor suppressor p53 , which can also bind to dna , stimulates the expression of other genes , such as waf1/cip1 encoding p21 8 , 22 . apc stabilizes microtubules to inhibit mitosis 15 and interferes with cell adhesion to its growing matrix 23 . the interference with cell adhesion results in indirect suppression of cell division due to contact inhibition . it has been observed that a few tumor suppressors may act in cooperation to inhibit cell mitosis 3 . tumor suppressors p15 , p16 , p18 , p19 , p21 and p27 inhibit cyclin - dependent kinases ( cdks ) , which , in turn , inhibit rb 11 , 24 . when cdks are inhibited , rb is kept active to suppress cell division 24 . arf is capable of relocating the murine double minute ( mdm2 ) , a critical negative regulator of p53 inhibitor , into nuclei to activate cellular p53 25 . histone methyltransferases are recently deemed as a special group of tumor suppressors , which can directly inhibit mitosis via changing the conformation of histone to block double - strand dna unwinding 26 . examples of this group of tumor suppressors are p53 , apc , cluster of differentiation 95 ( cd95 ) , bridging integrator 1 ( bin1 ) and phosphatase and tensin homolog ( pten ) 27 - 31 . unlike premature cell death , apoptosis maintains normal homeostasis and suppresses cancer 32 , 33 . p53 mediates apoptosis through two major pathways , the extrinsic pathway , which activates a caspase cascade including caspase-9 , -3 , -6 and -7 , and the intrinsic pathway , which promotes the apoptosome formation via the bcl-2 family 28 , 35 . apc , which has been observed to be frequently mutated in colorectal cancer , promotes transcription - independent apoptosis via caspase 8 27 . the apc - mediated apoptosis can be abolished by caspase-8 inhibitor z - ietd - fmk 27 . cd95 is overexpressed in cancer cells and acts as an important receptor for cell death 29 , 36 . upon being recognized immunogenically by a specific ligand expressed in the cytotoxic t killer cells bin1 , which is a cell death agent , mediates apoptosis to suppress cancer by c - myc 30 . in contrary to the above discussed tumor suppressors that directly induce apoptosis , pten utilizes an alternative mechanism to promote apoptosis . it inactivates phosphatidylinositol 3,4,5-triphosphate ( pip3 ) , which is important for anti - apoptosis and aids in cancer cell survival 31 . although some tumor suppressors can both inhibit mitosis and induce apoptosis , apoptosis is not necessarily induced by the inhibition of mitosis 38 . the tumor suppressors that can help in dna damage repair include muts homolog 2 ( msh2 ) , mutl homolog 1 ( mlh1 ) , ataxia - telangiectasia - mutated gene product ( atm ) , breast cancer protein ( brca ) , nijmegen breakage syndrome 1 ( nbs1 ) , fanconi - anemiarelated tumor suppressor ( fa ) , and p53 3 , 39 - 43 . they are able to fix dna damages , including mismatch and vast damage to one of the dna double strands . generally , p53 can induce nucleotide excision repair to remove damaged dna portions and mediate synthesis from the other strand ; whereas msh2 and mlh1 can repair dna mismatch 3 , 39 , 40 . atm is a general sensor to dna damage and phosphorylates p53 , brcp , nbs1 and fa to activate the dna repair process 3 , 41 . nbs1 and fa make dna resistant to crosslinking , and may amplify the phosphorylation signal from atm 43 . in addition , thymine - dna glycosylase ( tdg ) is proposed as a tumor suppressor candidate 44 - 46 . previous studies have shown that 5-methylation of cytosine could lead to spontaneous hydrolytic deamination to produce the ct transition mutation and t - g mismatches 44 - 46 . tdg recognizes the t - g mismatch , removes the mismatched t through hydrolysis of its n - glycosidic bond , and initiates a nucleotide excision repair 44 - 46 . the ct transition mutation happens frequently in human tumors and counts for about 24% of p53 mutations 44 , 47 - 50 . tumor cells have signal interactions with endothelial cells to initiate angiogenesis and break down vascular walls . tumor suppressors that can inhibit metastasis consist of metastin , breast cancer metastasis suppressor 1 ( brms1 ) , tissue inhibitor of metalloproteinase ( timp ) , cofactor required for specificity protein 1 activation ( crsp ) , and kal1/cd82 53 - 64 . the binding of metastin to the metastin receptor ( orphan g protein - coupled receptor gpr54 ) increases the expression and activity of focal adhesion kinase ( fak ) and inhibits the metastasis of melanoma cells 53 . it has also been shown that metastin triggers phospholipase c activation , arachidonic acid release and extracellular signal - regulated kinase ( erk ) phosphorylation in chinese hamster ovary ( cho ) cells overexpressing metastin receptor 54 , 55 . brms1 regulates gene transcription through interaction with the msin3 histone deacetylase ( hdac ) complex 57 . timps can bind not only all matrix metalloproteinases ( mmps ) in their active forms but also mmp-2 and mmp-9 in their latent forms . timps reduce cancer metastasis by inhibiting the cancer cell - released mmps , maintaining the integrity of extracellular matrices , and preventing the penetration of cancer cells through the base membrane of blood vessels 58 - 60 . the expression levels of cd82 and p53 are strongly correlated 63 . the exact mechanism for cd82 to inhibit cancer metastasis is still unclear ; however , it may inhibit cancer cell migration / invasion through the fak - lyn - p130-crkii pathway 64 . the tumor suppressors that adopt this mechanism include retinoblastoma protein ( rb ) , adenomatosis polyposis coli ( apc ) , alternate reading frame ( arf ) , riz1 , p15 , p16 , p18 , p19 , p21 , p27 , and p53 8 , 9 , 11 - 21 . rb , which is the first discovered tumor suppressor , inhibits the transcription of specific genes required for mitosis through binding to transcription factors such as e2fs , which are key cell proliferation regulators 12 , 13 . tumor suppressor p53 , which can also bind to dna , stimulates the expression of other genes , such as waf1/cip1 encoding p21 8 , 22 . apc stabilizes microtubules to inhibit mitosis 15 and interferes with cell adhesion to its growing matrix 23 . the interference with cell adhesion results in indirect suppression of cell division due to contact inhibition . it has been observed that a few tumor suppressors may act in cooperation to inhibit cell mitosis 3 . tumor suppressors p15 , p16 , p18 , p19 , p21 and p27 inhibit cyclin - dependent kinases ( cdks ) , which , in turn , inhibit rb 11 , 24 . arf is capable of relocating the murine double minute ( mdm2 ) , a critical negative regulator of p53 inhibitor , into nuclei to activate cellular p53 25 . histone methyltransferases are recently deemed as a special group of tumor suppressors , which can directly inhibit mitosis via changing the conformation of histone to block double - strand dna unwinding 26 . . examples of this group of tumor suppressors are p53 , apc , cluster of differentiation 95 ( cd95 ) , bridging integrator 1 ( bin1 ) and phosphatase and tensin homolog ( pten ) 27 - 31 . unlike premature cell death , apoptosis maintains normal homeostasis and suppresses cancer 32 , 33 . p53 mediates apoptosis through two major pathways , the extrinsic pathway , which activates a caspase cascade including caspase-9 , -3 , -6 and -7 , and the intrinsic pathway , which promotes the apoptosome formation via the bcl-2 family 28 , 35 . apc , which has been observed to be frequently mutated in colorectal cancer , promotes transcription - independent apoptosis via caspase 8 27 . the apc - mediated apoptosis can be abolished by caspase-8 inhibitor z - ietd - fmk 27 . cd95 is overexpressed in cancer cells and acts as an important receptor for cell death 29 , 36 . upon being recognized immunogenically by a specific ligand expressed in the cytotoxic t killer cells bin1 , which is a cell death agent , mediates apoptosis to suppress cancer by c - myc 30 . in contrary to the above discussed tumor suppressors that directly induce apoptosis , pten utilizes an alternative mechanism to promote apoptosis . it inactivates phosphatidylinositol 3,4,5-triphosphate ( pip3 ) , which is important for anti - apoptosis and aids in cancer cell survival 31 . although some tumor suppressors can both inhibit mitosis and induce apoptosis , apoptosis is not necessarily induced by the inhibition of mitosis 38 . the tumor suppressors that can help in dna damage repair include muts homolog 2 ( msh2 ) , mutl homolog 1 ( mlh1 ) , ataxia - telangiectasia - mutated gene product ( atm ) , breast cancer protein ( brca ) , nijmegen breakage syndrome 1 ( nbs1 ) , fanconi - anemiarelated tumor suppressor ( fa ) , and p53 3 , 39 - 43 . they are able to fix dna damages , including mismatch and vast damage to one of the dna double strands . generally , p53 can induce nucleotide excision repair to remove damaged dna portions and mediate synthesis from the other strand ; whereas msh2 and mlh1 can repair dna mismatch 3 , 39 , 40 . atm is a general sensor to dna damage and phosphorylates p53 , brcp , nbs1 and fa to activate the dna repair process 3 , 41 . nbs1 and fa make dna resistant to crosslinking , and may amplify the phosphorylation signal from atm 43 . in addition , thymine - dna glycosylase ( tdg ) is proposed as a tumor suppressor candidate 44 - 46 . previous studies have shown that 5-methylation of cytosine could lead to spontaneous hydrolytic deamination to produce the ct transition mutation and t - g mismatches 44 - 46 . tdg recognizes the t - g mismatch , removes the mismatched t through hydrolysis of its n - glycosidic bond , and initiates a nucleotide excision repair 44 - 46 . the ct transition mutation happens frequently in human tumors and counts for about 24% of p53 mutations 44 , 47 - 50 . tumor cells have signal interactions with endothelial cells to initiate angiogenesis and break down vascular walls . tumor suppressors that can inhibit metastasis consist of metastin , breast cancer metastasis suppressor 1 ( brms1 ) , tissue inhibitor of metalloproteinase ( timp ) , cofactor required for specificity protein 1 activation ( crsp ) , and kal1/cd82 53 - 64 . the binding of metastin to the metastin receptor ( orphan g protein - coupled receptor gpr54 ) increases the expression and activity of focal adhesion kinase ( fak ) and inhibits the metastasis of melanoma cells 53 . it has also been shown that metastin triggers phospholipase c activation , arachidonic acid release and extracellular signal - regulated kinase ( erk ) phosphorylation in chinese hamster ovary ( cho ) cells overexpressing metastin receptor 54 , 55 . brms1 regulates gene transcription through interaction with the msin3 histone deacetylase ( hdac ) complex 57 . timps can bind not only all matrix metalloproteinases ( mmps ) in their active forms but also mmp-2 and mmp-9 in their latent forms . timps reduce cancer metastasis by inhibiting the cancer cell - released mmps , maintaining the integrity of extracellular matrices , and preventing the penetration of cancer cells through the base membrane of blood vessels 58 - 60 . the expression levels of cd82 and p53 are strongly correlated 63 . the exact mechanism for cd82 to inhibit cancer metastasis is still unclear ; however , it may inhibit cancer cell migration / invasion through the fak - lyn - p130-crkii pathway 64 . in summary , we briefly reviewed the four major functional mechanisms for human tumor suppressors . some tumor suppressors , such as p53 , may utilize more than one mechanism for their suppressing functions . recent progress in structural and functional studies of tumor suppressors and their interactions with other molecules has benefited the design and discovery of novel anticancer agents . for example , quite a few cdk inhibitors have been developed and some are already in clinical trials .