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MINI-REVIEW
Cell Biology International 1998, Vol. 22, No. 6, 397–400 Article No. cb980329, available online at http://www.idealibrary.com on
MINI-REVIEW
Homeobox genes: A link between development, cell cycle, and cancer?
Heide L. Ford
Division of Cancer Biology, Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
During the past decade, much progress has been made in delineating the molecular alterations that lead to oncogenic transformation. Such research has clearly demonstrated that cancer results from the improper regulation of genes that control both cell growth and cell death. It has also become apparent that cancer and normal development have a great deal in common, as both processes involve shifts between cell proliferation and differentiation. This raises the question of the extent of interplay that exists between development, cell cycle, and cancer. Indeed, several genes are known to have a role in all three processes. Notably, pRb is a prototype tumor suppressor that acts as a ‘brake’ for cell cycle progression. Studies over the past few years have demonstrated that pRb is additionally involved in the differentiation of both muscle cells and adipocytes (see review, Jacks and Weinberg, 1998). The p21 cyclin dependent kinase inhibitor is also altered in a variety of cancers. It exerts an effect on the cell cycle by inhibiting both the G1/S and G2/M transitions, and was recently shown to play a role in keratinocyte differentiation (see review, Jacks and Weinberg, 1998). One can imagine how a gene involved in cell cycle control may have the same function in development, directing tissue specification by affecting cell growth. However, this is not always the case. Instead, the roles pRb and p21 play in differentiation and cell proliferation are distinct (see review, Jacks and Weinberg, 1998). Hence, these central regulatory 1065–6995/98/060397+04 $30.00/0
proteins rendered inactive in many cancers, are shared by development and cell cycle control, where they perform different functions. Evidence from our laboratory and others suggest that certain homeobox genes may provide an important link between the processes of cell cycle control, development, and cancer. Homeobox genes are transcription factors involved in normal differentiation and development, and were originally identified as genes whose mutations caused body segment transformation in Drosophila (Bridges and Morgan, 1923). Since then, more than 170 vertebrate homeobox genes have been found in a variety of species (Stein et al., 1996). All share a common sequence motif, the homeodomain. This motif is 183 nucleotides in length and encodes a 61-amino acid domain responsible for DNA binding (McGinnis and Krumlauff, 1992). It is through this DNA binding activity, and the subsequent transcriptional activation of downstream genes, that homeodomain-containing proteins are believed to exert their effects. The targets of mammalian homeobox proteins are not well known. It is postulated that they include genes encoding extracellular matrix proteins, adhesion molecules, and growth factors (Lawrence et al., 1996), families of genes important both for development and for tumorigenesis and metastasis. Further, an association exists between congenital anomalies, which often result from homeobox gene mutations, and cancer (Anbazhagan and Raman, 1997). Thus, it is not surprising that many homeobox genes have been implicated in carcinogenesis (for reviews see Cillo, 1994; Castronovo et al., 1994; Stuart and Gruss, 1995; Lawrence et al., 1996). Many cancers exhibit alterations in homeobox gene expression (see Table 1 for a partial listing). They include hematopoietic cancers, such as leukemias, where HOXA and HOXB members have altered expression levels (Lawrence et al., 1996), and breast, colon, prostate, and kidney cancers (including Wilms’ tumor), among others. Some of these tumors contain homeobox genes that have 1998 Academic Press
398
Cell Biology International, Vol. 22, No. 6, 1998
Table 1. Homeobox gene alterations in cancer Gene PAX2* PAX3 PAX5* PAX7 PAX8* HOXA1 HOXA9 HOXA10 HOXB5 HOXB7 HOXB8 HOXC11 HOXD4 HOX11 HSIX1 cdx 1,2 GBX2 PBX1
Cancer
Alteration
Wilms’ Rhabdomyosarcoma Glioblastoma Rhabdomyosarcoma Wilms’ thyroid Breast Myeloid leukemia Myeloid leukemia Renal Colorectal Myeloid leukemia Wilms’ Renal, colorectal T-cell leukemia Breast Colorectal Prostate Childhood leukemia
OE trans OE trans OE OE trans OE UE mRNA size OE OE mRNA size trans OE UE OE trans
References
} } }
See review Stuart and Gruss (1995) Chariot and Castronovo (1996) See review Lawrence et al. (1996) See review Cillo (1994) Lawrence et al. (1996) See review Cillo (1994) Hatano et al. (1991) Ford et al. (1998) Mallo et al. (1997) Gao et al. (1996) Nourse et al., 1990
*These genes contain only partial homeoboxes. OE—overexpressed, UE—underexpressed, trans—translocation, mRNA size—altered transcript size.
translocated to produce a fusion protein. In certain instances, the translocation produces a hybrid with a second transcription factor, presumably resulting in a gain of function. However, the precise mechanisms by which homeobox gene alterations lead to cancer are not known. Several homeobox genes are implicated in cell cycle control, a subset of which may be further involved in cancer. This suggests yet another mechanism by which altered expression of homeobox genes may lead to carcinogenesis. For example, the gax homeodomain protein induces p21 expression, which results in an increased association of p21 with cdk2, thereby inhibiting cellular proliferation (Smith et al., 1997). In addition, the cdk1 (cdc2) gene, which encodes the cyclin-dependent kinase important for the onset of mitosis, was recently shown to contain a homeobox protein binding site in its promoter (Liu and Bird, 1998). HOX11 and HSIX1 are examples of homeobox genes implicated in both cell cycle control and cancer. HOX11 was first isolated from a chromosomal breakpoint in human T-cell leukemia (Hatano et al., 1991), and was subsequently shown to cause cell cycle aberrations and tumorigenicity in transgenic mouse models when overexpressed in the thymus (Kawabe et al., 1997). Expression of the HOX11 homeobox gene is cell cycle regulated (Zhang et al., 1993), and it exerts its effect by binding to the catalytic subunit of both protein phosphatase 2A (PP2A) and protein phosphatase 1
(PP1) (Kawabe et al., 1997). This binding promotes progression into M-phase in both G2 arrested Xenopus oocytes and in Jurket cells arrested in G2 following DNA damage. Interestingly, HOX11 is able to bind PP2A and PP1 in the absence of the homeodomain (Kawabe et al., 1997), suggesting that it may affect the cell cycle independently of its putative role as a transcriptional activator. Homeobox genes are often expressed as alternatively spliced transcripts, where one transcript encodes a protein lacking the homeodomain (Magli et al., 1991). Although the roles of these homeodomain deficient isoforms are not known, it is postulated that they serve to modulate transcription by competing with the full length molecules for binding to other factors (Stern and Herr, 1991). An attractive alternative hypothesis is that the truncated proteins may have roles unrelated to transcription, as is suggested for HOX11. This would result in dual functions, evolved for utilization in both development and cell cycle control. The HSIX1 homeobox gene was identified in our laboratory as a gene that is differentially expressed in the cell cycle of mammary carcinoma cells. HSIX1 mRNA was undetectable at the onset, but expressed towards the end, of S-phase, thus linking yet another homeobox gene to cell cycle control (Ford et al., 1998). Its mouse counterpart was originally cloned by homology to the Drosophila sine oculis (so) gene (Oliver et al., 1995), a protein that plays a role in Drosophila eye development,
Cell Biology International, Vol. 22, No. 6, 1998
where cells coordinately progress through the cell cycle (Cheyette et al., 1994). Sine oculis itself is expressed prior to a mitotic wave, and is postulated to be involved in synchronization of the cell cycle (Cheyette et al., 1994). The expression pattern of HSIX1 in the cell cycle of mammary carcinoma cells and its homology to sine oculis suggest that it plays a role in regulating the onset of mitosis. Indeed, overexpression of HSIX1 abrogates an irradiation induced G2 cell cycle arrest, promoting earlier entry into mitosis (Ford et al., 1998), as is observed with HOX11. Furthermore, HSIX1, as HOX11, is aberrantly expressed in cancer. Its expression is absent in a normal mammary epithelial cell line (70N), but is present at various levels in a progressive series of mammary carcinoma cell lines developed from the same patient (21T series). Higher levels of HSIX1 expression are observed in cell lines derived from the metastatic lesions (21MT1 and 21MT2) than in those derived from the primary tumor (21PT and 21NT). In addition, overexpression of HSIX1 is observed in 44% of primary and 90% of metastatic breast lesions, suggesting that HSIX1 may play a role in the progression of breast cancer (Ford et al., 1998). Attenuation of a G2 checkpoint, such as observed in both HOX11 and HSIX1 overexpressing cell lines, could lead to cancer by allowing cells to progress through cell division without repairing damaged DNA. This would result in the transmission of mutations into subsequent generations, increasing the probability of cancer. Diseases such as ataxia-telangiectasia (Scott et al., 1994), Li-Fraumeni syndrome (Paules et al., 1995), Bloom’s Syndrome (Davey et al., 1998), and Fanconi anemia (Kupfer and D’Andrea, 1996) are all associated with defects in the G2 checkpoint and cancer susceptibility. Interestingly, of the existing examples of homeobox genes involved in cell cycle control, several appear to play a role in the G2/M transition. Work by Stukenberg and colleagues (1997) demonstrates yet another connection between proteins encoded by homeobox genes and G2/M. They identified five homeodomain containing proteins that were specifically phosphorylated in mitosis. Mitotic phosphoproteins are thought to be downstream targets of cyclin dependent kinases, and their phosphorylation is presumed important for cell division. While it was speculated that phosphorylation of these transcription factors serves to remove the proteins from chromatin before cell division, it is also possible that their phosphorylation may activate a secondary function of the homeobox
399
gene, one that is necessary for progression through mitosis. Further research must be performed to understand the integration between homeobox genes, cell cycle, and cancer. Several questions deserve immediate attention. First, how general is the function of homeobox genes in the cell cycle? Is there a role for the cell cycle functions of the homeobox genes in development, or are the roles in the two processes distinct? Is the transcriptional activity of a particular homeobox protein (through its homeodomain) important for all of its functions, or may it have separate functions which do not require the homeodomain? Finally, what, if any, is the role of the homeobox gene in cancer, and are the cell cycle functions of their encoded proteins important in tumor progression? Although many questions remain, it is increasingly evident that development, cell cycle, and cancer are intimately linked, and that homeobox genes may be an important point of convergence.
ACKNOWLEDGEMENTS A special thanks to Dr Arthur Pardee, under whose guidance I have performed the HSIX1-related work. The research was funded by Grant CA61253 from the National Institutes of Health. HLF was supported by the Dana-Farber Cancer Institute Tumor Biology Grant T32-CA09361. REFERENCES A R, R V, 1997. Homeobox genes: Molecular link between congenital anomalies and cancer. Eur J Cancer 33: 635–637. B CB, M TH, 1923. The third chromosome group of mutant characters of Drosophila melanogaster. Carnegie Inst Wash 327: 93. C A, C V, 1996. Detection of HOXA1 expression in human breast cancer. Biochem Biophys Res Commun 222: 292–297. C V, K M, C A, G J, S M, 1994. Homeobox genes: Potential candidates for the transcriptional control of the transformed and invasive phenotype. Biochem Pharmacol 47: 137–143. C BNR, G PJ, M K, G H, H V, Z SL, 1994. The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12: 977–996. C C, 1994. HOX genes in human cancers. Invasion Metastasis 14: 38–49. D S, H CS, R SA, K JC, J A, E A, H KM, L HB, F GA,
400
1998. Fission yeast RAD12(+) regulates cell cycle checkpoint control and is homologous to the Blooms-syndrome disease gene. Mol Cell Biol 18: 2721–2728. F HL, K EK, B EA, M GL, P AB, 1998. Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: A possible mechanism of breast carcinogenesis. Proc Natl Acad Sci USA 95: 12,608– 12,613. G AC, I JT, 1996. Expression of the homeobox gene-GBX2 in human prostate cancer cells. Prostate 29: 395–398. H M, R CW, M M, C WM, K SJ, 1991. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253: 79–82. J T, W RA, 1998. The expanding role of cell cycle regulators. Science 280: 1035–1037. K T, M AJ, K S, 1997. HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. Nature 385: 454–458. K GM, D’A AD, 1996. The effect of the Fanconi Anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation. Blood 88: 1019–1025. L HJ, S G, H RK, L C, 1996. The Role of HOX Homeobox Genes in Normal and Leukemic Hematapoiesis. Stem Cells 14: 281–291. L H, B C, 1998. Characterization of the enhancer-like okadaic acid response element region of the cyclindependent kinase 1 (p34cdc2) promoter. Biochem Biophys Res Commun 246: 696–702. M MC, B P, C A, DV G, C C, B E, 1991. Coordinate regulation of HOX genes in human hematopoietic cells. Proc Natl Acad Sci USA 88: 6348–6353. M GV, R H, F J-M, R D, Z A, L M, J BR, D NJ, D J-C, I JL, 1997. Molecular cloning, sequencing and expression of the MRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int J Cancer 74: 35–44.
Cell Biology International, Vol. 22, No. 6, 1998
MG W, K R, 1992. Homeobox genes and axial patterning. Cell 68: 283–302. N J, M JD, G N, W J, S E, S SD, C ML, 1990. Chromosomal translocation t (1:19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60: 535–546. O G, W R, J NA, C BG, C BNR, H V, Z SL, G P, 1995. Homeobox genes and connective tissue patterning. Development 121: 693–705. P RS, L EN, W SJ, I CL, R N, T TD, G DA, D LA, T MA, K WK, 1995. Defective G(2) checkpoint function in cells from individuals with familial cancer syndromes. Cancer Res 55: 1763–1773. S D, S AR, R SA, 1994. Radiationinduced G(2) delay and spontaneous chromosome aberrations in ataxia-telangiectasia homozygotes and heterozygotes. Int J Radiation Biol 66: S157–S163. S RC, B D, G DH, G K, P H, D J-F, P C, M A, D P, I JM, W K, 1997. p21CIP1-Mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene. Genes Dev 11: 1674–1689. S S, F R, L L, K M, 1996. Checklist: Vertebrate homeobox genes. Mech Develop 55: 91–108. S S, H W, 1991. The herpes simplex virus transactivator VP16 recognizes the Oct-1 homeodomain: evidence for a homeodomain recognition subdomain. Genes Dev 5: 2555–2563. S ET, G P, 1995. PAX genes: what’s new in developmental biology and cancer? Human Mol Genet 4: 1717–1720. S PT, L KD, MG TJ, K RW, K J, K MW, 1997. Systematic identification of mitotic phosphoproteins. Curr Biol 7: 338–348. Z N, G Z-Z, M M, L M, 1993. The HOX-11 (TCL-3) homeobox proto-oncogene encodes a nuclear protein that undergoes cell cycle-dependent regulation. Oncogene 8: 3265–3270.
MINI-REVIEW
Homeobox genes: A link between development, cell cycle, and cancer?
Heide L. Ford
Division of Cancer Biology, Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
During the past decade, much progress has been made in delineating the molecular alterations that lead to oncogenic transformation. Such research has clearly demonstrated that cancer results from the improper regulation of genes that control both cell growth and cell death. It has also become apparent that cancer and normal development have a great deal in common, as both processes involve shifts between cell proliferation and differentiation. This raises the question of the extent of interplay that exists between development, cell cycle, and cancer. Indeed, several genes are known to have a role in all three processes. Notably, pRb is a prototype tumor suppressor that acts as a ‘brake’ for cell cycle progression. Studies over the past few years have demonstrated that pRb is additionally involved in the differentiation of both muscle cells and adipocytes (see review, Jacks and Weinberg, 1998). The p21 cyclin dependent kinase inhibitor is also altered in a variety of cancers. It exerts an effect on the cell cycle by inhibiting both the G1/S and G2/M transitions, and was recently shown to play a role in keratinocyte differentiation (see review, Jacks and Weinberg, 1998). One can imagine how a gene involved in cell cycle control may have the same function in development, directing tissue specification by affecting cell growth. However, this is not always the case. Instead, the roles pRb and p21 play in differentiation and cell proliferation are distinct (see review, Jacks and Weinberg, 1998). Hence, these central regulatory 1065–6995/98/060397+04 $30.00/0
proteins rendered inactive in many cancers, are shared by development and cell cycle control, where they perform different functions. Evidence from our laboratory and others suggest that certain homeobox genes may provide an important link between the processes of cell cycle control, development, and cancer. Homeobox genes are transcription factors involved in normal differentiation and development, and were originally identified as genes whose mutations caused body segment transformation in Drosophila (Bridges and Morgan, 1923). Since then, more than 170 vertebrate homeobox genes have been found in a variety of species (Stein et al., 1996). All share a common sequence motif, the homeodomain. This motif is 183 nucleotides in length and encodes a 61-amino acid domain responsible for DNA binding (McGinnis and Krumlauff, 1992). It is through this DNA binding activity, and the subsequent transcriptional activation of downstream genes, that homeodomain-containing proteins are believed to exert their effects. The targets of mammalian homeobox proteins are not well known. It is postulated that they include genes encoding extracellular matrix proteins, adhesion molecules, and growth factors (Lawrence et al., 1996), families of genes important both for development and for tumorigenesis and metastasis. Further, an association exists between congenital anomalies, which often result from homeobox gene mutations, and cancer (Anbazhagan and Raman, 1997). Thus, it is not surprising that many homeobox genes have been implicated in carcinogenesis (for reviews see Cillo, 1994; Castronovo et al., 1994; Stuart and Gruss, 1995; Lawrence et al., 1996). Many cancers exhibit alterations in homeobox gene expression (see Table 1 for a partial listing). They include hematopoietic cancers, such as leukemias, where HOXA and HOXB members have altered expression levels (Lawrence et al., 1996), and breast, colon, prostate, and kidney cancers (including Wilms’ tumor), among others. Some of these tumors contain homeobox genes that have 1998 Academic Press
398
Cell Biology International, Vol. 22, No. 6, 1998
Table 1. Homeobox gene alterations in cancer Gene PAX2* PAX3 PAX5* PAX7 PAX8* HOXA1 HOXA9 HOXA10 HOXB5 HOXB7 HOXB8 HOXC11 HOXD4 HOX11 HSIX1 cdx 1,2 GBX2 PBX1
Cancer
Alteration
Wilms’ Rhabdomyosarcoma Glioblastoma Rhabdomyosarcoma Wilms’ thyroid Breast Myeloid leukemia Myeloid leukemia Renal Colorectal Myeloid leukemia Wilms’ Renal, colorectal T-cell leukemia Breast Colorectal Prostate Childhood leukemia
OE trans OE trans OE OE trans OE UE mRNA size OE OE mRNA size trans OE UE OE trans
References
} } }
See review Stuart and Gruss (1995) Chariot and Castronovo (1996) See review Lawrence et al. (1996) See review Cillo (1994) Lawrence et al. (1996) See review Cillo (1994) Hatano et al. (1991) Ford et al. (1998) Mallo et al. (1997) Gao et al. (1996) Nourse et al., 1990
*These genes contain only partial homeoboxes. OE—overexpressed, UE—underexpressed, trans—translocation, mRNA size—altered transcript size.
translocated to produce a fusion protein. In certain instances, the translocation produces a hybrid with a second transcription factor, presumably resulting in a gain of function. However, the precise mechanisms by which homeobox gene alterations lead to cancer are not known. Several homeobox genes are implicated in cell cycle control, a subset of which may be further involved in cancer. This suggests yet another mechanism by which altered expression of homeobox genes may lead to carcinogenesis. For example, the gax homeodomain protein induces p21 expression, which results in an increased association of p21 with cdk2, thereby inhibiting cellular proliferation (Smith et al., 1997). In addition, the cdk1 (cdc2) gene, which encodes the cyclin-dependent kinase important for the onset of mitosis, was recently shown to contain a homeobox protein binding site in its promoter (Liu and Bird, 1998). HOX11 and HSIX1 are examples of homeobox genes implicated in both cell cycle control and cancer. HOX11 was first isolated from a chromosomal breakpoint in human T-cell leukemia (Hatano et al., 1991), and was subsequently shown to cause cell cycle aberrations and tumorigenicity in transgenic mouse models when overexpressed in the thymus (Kawabe et al., 1997). Expression of the HOX11 homeobox gene is cell cycle regulated (Zhang et al., 1993), and it exerts its effect by binding to the catalytic subunit of both protein phosphatase 2A (PP2A) and protein phosphatase 1
(PP1) (Kawabe et al., 1997). This binding promotes progression into M-phase in both G2 arrested Xenopus oocytes and in Jurket cells arrested in G2 following DNA damage. Interestingly, HOX11 is able to bind PP2A and PP1 in the absence of the homeodomain (Kawabe et al., 1997), suggesting that it may affect the cell cycle independently of its putative role as a transcriptional activator. Homeobox genes are often expressed as alternatively spliced transcripts, where one transcript encodes a protein lacking the homeodomain (Magli et al., 1991). Although the roles of these homeodomain deficient isoforms are not known, it is postulated that they serve to modulate transcription by competing with the full length molecules for binding to other factors (Stern and Herr, 1991). An attractive alternative hypothesis is that the truncated proteins may have roles unrelated to transcription, as is suggested for HOX11. This would result in dual functions, evolved for utilization in both development and cell cycle control. The HSIX1 homeobox gene was identified in our laboratory as a gene that is differentially expressed in the cell cycle of mammary carcinoma cells. HSIX1 mRNA was undetectable at the onset, but expressed towards the end, of S-phase, thus linking yet another homeobox gene to cell cycle control (Ford et al., 1998). Its mouse counterpart was originally cloned by homology to the Drosophila sine oculis (so) gene (Oliver et al., 1995), a protein that plays a role in Drosophila eye development,
Cell Biology International, Vol. 22, No. 6, 1998
where cells coordinately progress through the cell cycle (Cheyette et al., 1994). Sine oculis itself is expressed prior to a mitotic wave, and is postulated to be involved in synchronization of the cell cycle (Cheyette et al., 1994). The expression pattern of HSIX1 in the cell cycle of mammary carcinoma cells and its homology to sine oculis suggest that it plays a role in regulating the onset of mitosis. Indeed, overexpression of HSIX1 abrogates an irradiation induced G2 cell cycle arrest, promoting earlier entry into mitosis (Ford et al., 1998), as is observed with HOX11. Furthermore, HSIX1, as HOX11, is aberrantly expressed in cancer. Its expression is absent in a normal mammary epithelial cell line (70N), but is present at various levels in a progressive series of mammary carcinoma cell lines developed from the same patient (21T series). Higher levels of HSIX1 expression are observed in cell lines derived from the metastatic lesions (21MT1 and 21MT2) than in those derived from the primary tumor (21PT and 21NT). In addition, overexpression of HSIX1 is observed in 44% of primary and 90% of metastatic breast lesions, suggesting that HSIX1 may play a role in the progression of breast cancer (Ford et al., 1998). Attenuation of a G2 checkpoint, such as observed in both HOX11 and HSIX1 overexpressing cell lines, could lead to cancer by allowing cells to progress through cell division without repairing damaged DNA. This would result in the transmission of mutations into subsequent generations, increasing the probability of cancer. Diseases such as ataxia-telangiectasia (Scott et al., 1994), Li-Fraumeni syndrome (Paules et al., 1995), Bloom’s Syndrome (Davey et al., 1998), and Fanconi anemia (Kupfer and D’Andrea, 1996) are all associated with defects in the G2 checkpoint and cancer susceptibility. Interestingly, of the existing examples of homeobox genes involved in cell cycle control, several appear to play a role in the G2/M transition. Work by Stukenberg and colleagues (1997) demonstrates yet another connection between proteins encoded by homeobox genes and G2/M. They identified five homeodomain containing proteins that were specifically phosphorylated in mitosis. Mitotic phosphoproteins are thought to be downstream targets of cyclin dependent kinases, and their phosphorylation is presumed important for cell division. While it was speculated that phosphorylation of these transcription factors serves to remove the proteins from chromatin before cell division, it is also possible that their phosphorylation may activate a secondary function of the homeobox
399
gene, one that is necessary for progression through mitosis. Further research must be performed to understand the integration between homeobox genes, cell cycle, and cancer. Several questions deserve immediate attention. First, how general is the function of homeobox genes in the cell cycle? Is there a role for the cell cycle functions of the homeobox genes in development, or are the roles in the two processes distinct? Is the transcriptional activity of a particular homeobox protein (through its homeodomain) important for all of its functions, or may it have separate functions which do not require the homeodomain? Finally, what, if any, is the role of the homeobox gene in cancer, and are the cell cycle functions of their encoded proteins important in tumor progression? Although many questions remain, it is increasingly evident that development, cell cycle, and cancer are intimately linked, and that homeobox genes may be an important point of convergence.
ACKNOWLEDGEMENTS A special thanks to Dr Arthur Pardee, under whose guidance I have performed the HSIX1-related work. The research was funded by Grant CA61253 from the National Institutes of Health. HLF was supported by the Dana-Farber Cancer Institute Tumor Biology Grant T32-CA09361. REFERENCES A R, R V, 1997. Homeobox genes: Molecular link between congenital anomalies and cancer. Eur J Cancer 33: 635–637. B CB, M TH, 1923. The third chromosome group of mutant characters of Drosophila melanogaster. Carnegie Inst Wash 327: 93. C A, C V, 1996. Detection of HOXA1 expression in human breast cancer. Biochem Biophys Res Commun 222: 292–297. C V, K M, C A, G J, S M, 1994. Homeobox genes: Potential candidates for the transcriptional control of the transformed and invasive phenotype. Biochem Pharmacol 47: 137–143. C BNR, G PJ, M K, G H, H V, Z SL, 1994. The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12: 977–996. C C, 1994. HOX genes in human cancers. Invasion Metastasis 14: 38–49. D S, H CS, R SA, K JC, J A, E A, H KM, L HB, F GA,
400
1998. Fission yeast RAD12(+) regulates cell cycle checkpoint control and is homologous to the Blooms-syndrome disease gene. Mol Cell Biol 18: 2721–2728. F HL, K EK, B EA, M GL, P AB, 1998. Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: A possible mechanism of breast carcinogenesis. Proc Natl Acad Sci USA 95: 12,608– 12,613. G AC, I JT, 1996. Expression of the homeobox gene-GBX2 in human prostate cancer cells. Prostate 29: 395–398. H M, R CW, M M, C WM, K SJ, 1991. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253: 79–82. J T, W RA, 1998. The expanding role of cell cycle regulators. Science 280: 1035–1037. K T, M AJ, K S, 1997. HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. Nature 385: 454–458. K GM, D’A AD, 1996. The effect of the Fanconi Anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation. Blood 88: 1019–1025. L HJ, S G, H RK, L C, 1996. The Role of HOX Homeobox Genes in Normal and Leukemic Hematapoiesis. Stem Cells 14: 281–291. L H, B C, 1998. Characterization of the enhancer-like okadaic acid response element region of the cyclindependent kinase 1 (p34cdc2) promoter. Biochem Biophys Res Commun 246: 696–702. M MC, B P, C A, DV G, C C, B E, 1991. Coordinate regulation of HOX genes in human hematopoietic cells. Proc Natl Acad Sci USA 88: 6348–6353. M GV, R H, F J-M, R D, Z A, L M, J BR, D NJ, D J-C, I JL, 1997. Molecular cloning, sequencing and expression of the MRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int J Cancer 74: 35–44.
Cell Biology International, Vol. 22, No. 6, 1998
MG W, K R, 1992. Homeobox genes and axial patterning. Cell 68: 283–302. N J, M JD, G N, W J, S E, S SD, C ML, 1990. Chromosomal translocation t (1:19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60: 535–546. O G, W R, J NA, C BG, C BNR, H V, Z SL, G P, 1995. Homeobox genes and connective tissue patterning. Development 121: 693–705. P RS, L EN, W SJ, I CL, R N, T TD, G DA, D LA, T MA, K WK, 1995. Defective G(2) checkpoint function in cells from individuals with familial cancer syndromes. Cancer Res 55: 1763–1773. S D, S AR, R SA, 1994. Radiationinduced G(2) delay and spontaneous chromosome aberrations in ataxia-telangiectasia homozygotes and heterozygotes. Int J Radiation Biol 66: S157–S163. S RC, B D, G DH, G K, P H, D J-F, P C, M A, D P, I JM, W K, 1997. p21CIP1-Mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene. Genes Dev 11: 1674–1689. S S, F R, L L, K M, 1996. Checklist: Vertebrate homeobox genes. Mech Develop 55: 91–108. S S, H W, 1991. The herpes simplex virus transactivator VP16 recognizes the Oct-1 homeodomain: evidence for a homeodomain recognition subdomain. Genes Dev 5: 2555–2563. S ET, G P, 1995. PAX genes: what’s new in developmental biology and cancer? Human Mol Genet 4: 1717–1720. S PT, L KD, MG TJ, K RW, K J, K MW, 1997. Systematic identification of mitotic phosphoproteins. Curr Biol 7: 338–348. Z N, G Z-Z, M M, L M, 1993. The HOX-11 (TCL-3) homeobox proto-oncogene encodes a nuclear protein that undergoes cell cycle-dependent regulation. Oncogene 8: 3265–3270.