* 116957

RB TRANSCRIPTIONAL COREPRESSOR-LIKE 1; RBL1


Alternative titles; symbols

RETINOBLASTOMA-LIKE 1
CELLULAR PROTEIN p107; CP107; p107


HGNC Approved Gene Symbol: RBL1

Cytogenetic location: 20q11.23     Genomic coordinates (GRCh38): 20:36,996,349-37,095,997 (from NCBI)


TEXT

Cloning and Expression

Ewen et al. (1991) obtained a partial cDNA for human RBL1, which they called p107. The cDNA encodes a 936-residue protein. Comparison with RB1 (614041) showed a major region of homology extending over 564 residues. This region in RB1 is essential to its growth-controlling function. Sequences outside of this region are largely unique to each protein.

Kim et al. (1995) showed that the 4.9- and 2.4-kb Rbl1 transcripts of the fetal mouse are a consequence of alternative splicing. The larger message encodes a 119-kD protein and the smaller a 68-kD protein.

Huppi et al. (1996) cloned the mouse Rbl1 gene and compared its sequence with its human counterpart. The extreme N-terminal and C-terminal regions are the most conserved between the 2 sequences.

Using in situ hybridization, Vanderluit et al. (2004) found that p107 was expressed in a few select cells along the lateral ventricles of adult mice. Western blot analysis detected p107 expression in neural precursor cells from wildtype embryonic day-10 and adult neurospheres, which are derived from multipotent stem cells.


Gene Function

The cellular protein p107, like RB1, had been shown to form a specific complex with adenovirus E1A and SV40 large T antigen (T). The binding characteristics implied that RB1 and p107 share a common biochemical function (Ewen et al., 1991).

SMAD3 (603109) is a direct mediator of transcriptional activation by the TGF-beta (190180) receptor (see 190181). Its target genes in epithelial cells include cyclin-dependent kinase (CDK; see 116953) inhibitors that generate a cytostatic response. Chen et al. (2002) defined how, in the same context, SMAD3 can mediate transcriptional repression of the growth-promoting gene MYC (190080). A complex containing SMAD3, the transcription factors E2F4 (600659), E2F5 (600967), and DP1 (189902), and the corepressor p107 preexists in the cytoplasm. In response to TGF-beta, this complex moves into the nucleus and associates with SMAD4 (600993), recognizing a composite SMAD-E2F site on MYC for repression. Previously known as the ultimate recipients of CDK regulatory signals, E2F4/E2F5 and p107 act here as transducers of TGF-beta receptor signals upstream of CDK. SMAD proteins therefore mediate transcriptional activation or repression depending on their associated partners.

Williams et al. (2006) found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (190020) allele than wildtype cells. Depletion of RB from HRAS-transformed mouse cells or human tumor cells harboring HRAS pathway mutations inhibited their proliferation and anchorage-independent growth. In contrast to Rb -/- mouse fibroblasts, p107 -/- and p130 (RBL2; 180203) -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells. Moreover, loss of RB in human tumor cells harboring an HRAS mutation resulted in increased expression of p107, and overexpression of p107, but not RB, strongly inhibited proliferation of these tumor cells. Williams et al. (2006) concluded that RB and p107 have distinct roles in HRAS-mediated transformation and that p107 has a role as a tumor suppressor in the context of activated HRAS.

Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E (see CCNE1; 123837)-CDK2 pathway, including Cdkn1a (116899), Rb1, Rbl1, Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.


Gene Structure

Ichimura et al. (2000) determined that the RBL1 gene contains 22 exons and spans more than 100 kb.


Mapping

Ewen et al. (1991) used a partial cDNA for human p107 to map the gene to 20q11.2 by fluorescence in situ hybridization.

Huppi et al. (1996) found that the mouse Rbl1 gene maps to the distal end of chromosome 2, as does also the E2f1 gene (189971).


Animal Model

LeCouter et al. (1998) introduced a null mutation in p107 into the germ line of mice and bred into a BALB/cJ genetic background. Mice lacking p107 were viable and fertile but displayed impaired growth, reaching about 50% of normal weight by 21 days of age. Mutant mice exhibited a myeloproliferative disorder characterized by ectopic myeloid hyperplasia in the spleen and liver. Embryonic p107 -/- fibroblasts and primary myoblasts isolated from adult p107 -/- mice displayed a striking 2-fold acceleration in doubling time. However, cell sort analysis indicated that the fraction of cells in G1, S, and G2 was unaltered, suggesting that the different phases of the cell cycle in p107 -/- cells was uniformly reduced by a factor of 2. Western analysis of cyclin expression in synchronized p107 -/- fibroblasts revealed that expression of cyclins E and A preceded that of D1. Mutant embryos expressed approximately twice the normal levels of Rb, whereas p130 levels were unaltered. Finally, mutant mice reverted to a wildtype phenotype following a single backcross with C57BL/6J mice, suggesting the existence of modifier genes that have potentially epistatic relationships with p107. LeCouter et al. (1998) concluded that p107 has an important role in negatively regulating the rate of progression of the cell cycle, but in a strain-dependent manner.

To examine the role of p107 in mouse lateral ventricles, Vanderluit et al. (2004) developed p107-null mice. Adult mutant mice had elevated numbers of proliferating progenitor cells in their lateral ventricles. In vitro neurosphere assays revealed an increase in the number of neurosphere-forming cells from p107 -/- brains that exhibited enhanced capacity for self-renewal. An expanded stem cell population in p107-deficient mice was indicated in vivo by increased numbers of slowly cycling cells in the lateral ventricles and accelerated rates of neural precursor repopulation after progenitor ablation. Notch1 (190198) was upregulated in mutant neurospheres in vitro and brains in vivo. Chromatin immunoprecipitation and p107 overexpression suggested that p107 may modulate the Notch1 pathway. Vanderluit et al. (2004) concluded that p107 negatively regulates the number of neural stem cells in developing and adult brain, a function distinct from that of Rb.

Haigis et al. (2006) found that Rb was expressed in all epithelial cells of mouse colon, whereas p107 was expressed predominantly in the lower half of the crypt, and p130 was expressed in the upper portion of the crypt and in the epithelium lining the lumen. Similarly, undifferentiated cells in the mouse small intestinal crypt expressed Rb and p107, whereas differentiated cells in the villi expressed Rb and p130. Conditional deletion of Rb or p130 increased p107 levels, and Rb/p130 double mutants had even higher levels of p107. Although mutating any of these 3 genes singly had little or no effect, loss of Rb and p107 or p130 together produced chronic hyperplasia and dysplasia of the small intestinal and colonic epithelium. In Rb/p130 double mutants, this hyperplasia was associated with defects in terminal differentiation of specific cell types and was dependent on the increased proliferation seen in the epithelium of mutant animals.


REFERENCES

  1. Chen, C.-R., Kang, Y., Siegel, P. M., Massague, J. E2F4/5 and p107 as Smad cofactors linking the TGF-beta receptor to c-myc repression. Cell 110: 19-32, 2002. [PubMed: 12150994, related citations] [Full Text]

  2. Ewen, M. E., Xing, Y., Lawrence, J. B., Livingston, D. M. Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell 66: 1155-1164, 1991. [PubMed: 1833063, related citations] [Full Text]

  3. Haigis, K., Sage, J., Glickman, J., Shafer, S., Jacks, T. The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium. J. Biol. Chem. 281: 638-647, 2006. [PubMed: 16258171, related citations] [Full Text]

  4. Huppi, K., Siwarski, D., Mock, B. A., Dosik, J., Hamel, P. A. Molecular cloning, chromosomal mapping, and expression of the mouse p107 gene. Mammalian Genome 7: 353-355, 1996. [PubMed: 8661722, related citations] [Full Text]

  5. Ichimura, K., Hanafusa, H., Takimoto, H., Ohgama, Y., Akagi, T., Shimizu, K. Structure of the human retinoblastoma-related p107 gene and its intragenic deletion in a B-cell lymphoma cell line. Gene 251: 37-43, 2000. [PubMed: 10863094, related citations] [Full Text]

  6. Kim, K. K., Soonpaa, M. H., Wang, H., Field, L. J. Developmental expression of p107 mRNA and evidence for alternative splicing of the p107 (RBL1) gene product. Genomics 28: 520-529, 1995. [PubMed: 7490090, related citations] [Full Text]

  7. LeCouter, J. E., Kablar, B., Hardy, W. R., Ying, C., Megeney, L. A., May, L. L., Rudnicki, M. A. Strain-dependent myeloid hyperplasia, growth deficiency, and accelerated cell cycle in mice lacking the Rb-related p107 gene. Molec. Cell. Biol. 18: 7455-7465, 1998. [PubMed: 9819431, images, related citations] [Full Text]

  8. Vanderluit, J. L., Ferguson, K. L., Nikoletopoulou, V., Parker, M., Ruzhynsky, V., Alexson, T., McNamara, S. M., Park, D. S., Rudnicki, M., Slack, R. S. p107 regulates neural precursor cells in the mammalian brain. J. Cell Biol. 166: 853-863, 2004. [PubMed: 15353549, images, related citations] [Full Text]

  9. Wang, Y., Baskerville, S., Shenoy, A., Babiarz, J. E., Baehner, L., Blelloch, R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nature Genet. 40: 1478-1483, 2008. [PubMed: 18978791, images, related citations] [Full Text]

  10. Williams, J. P., Stewart, T., Li, B., Mulloy, R., Dimova, D., Classon, M. The retinoblastoma protein is required for Ras-induced oncogenic transformation. Molec. Cell. Biol. 26: 1170-1182, 2006. [PubMed: 16449633, images, related citations] [Full Text]


Patricia A. Hartz - updated : 2/11/2009
Patricia A. Hartz - updated : 9/19/2007
Patricia A. Hartz - updated : 2/24/2005
Stylianos E. Antonarakis - updated : 7/26/2002
Ada Hamosh - updated : 8/18/2000
Alan F. Scott - updated : 9/27/1995
Creation Date:
Victor A. McKusick : 10/4/1991
carol : 01/10/2022
carol : 06/17/2011
mgross : 2/16/2009
terry : 2/11/2009
mgross : 10/9/2007
terry : 9/19/2007
terry : 9/19/2007
alopez : 8/3/2006
terry : 8/1/2006
mgross : 2/24/2005
mgross : 7/26/2002
mgross : 7/26/2002
alopez : 10/12/2000
terry : 8/18/2000
terry : 6/13/1996
terry : 6/11/1996
terry : 4/17/1996
mark : 3/7/1996
carol : 4/19/1994
supermim : 3/16/1992
carol : 10/4/1991

* 116957

RB TRANSCRIPTIONAL COREPRESSOR-LIKE 1; RBL1


Alternative titles; symbols

RETINOBLASTOMA-LIKE 1
CELLULAR PROTEIN p107; CP107; p107


HGNC Approved Gene Symbol: RBL1

Cytogenetic location: 20q11.23     Genomic coordinates (GRCh38): 20:36,996,349-37,095,997 (from NCBI)


TEXT

Cloning and Expression

Ewen et al. (1991) obtained a partial cDNA for human RBL1, which they called p107. The cDNA encodes a 936-residue protein. Comparison with RB1 (614041) showed a major region of homology extending over 564 residues. This region in RB1 is essential to its growth-controlling function. Sequences outside of this region are largely unique to each protein.

Kim et al. (1995) showed that the 4.9- and 2.4-kb Rbl1 transcripts of the fetal mouse are a consequence of alternative splicing. The larger message encodes a 119-kD protein and the smaller a 68-kD protein.

Huppi et al. (1996) cloned the mouse Rbl1 gene and compared its sequence with its human counterpart. The extreme N-terminal and C-terminal regions are the most conserved between the 2 sequences.

Using in situ hybridization, Vanderluit et al. (2004) found that p107 was expressed in a few select cells along the lateral ventricles of adult mice. Western blot analysis detected p107 expression in neural precursor cells from wildtype embryonic day-10 and adult neurospheres, which are derived from multipotent stem cells.


Gene Function

The cellular protein p107, like RB1, had been shown to form a specific complex with adenovirus E1A and SV40 large T antigen (T). The binding characteristics implied that RB1 and p107 share a common biochemical function (Ewen et al., 1991).

SMAD3 (603109) is a direct mediator of transcriptional activation by the TGF-beta (190180) receptor (see 190181). Its target genes in epithelial cells include cyclin-dependent kinase (CDK; see 116953) inhibitors that generate a cytostatic response. Chen et al. (2002) defined how, in the same context, SMAD3 can mediate transcriptional repression of the growth-promoting gene MYC (190080). A complex containing SMAD3, the transcription factors E2F4 (600659), E2F5 (600967), and DP1 (189902), and the corepressor p107 preexists in the cytoplasm. In response to TGF-beta, this complex moves into the nucleus and associates with SMAD4 (600993), recognizing a composite SMAD-E2F site on MYC for repression. Previously known as the ultimate recipients of CDK regulatory signals, E2F4/E2F5 and p107 act here as transducers of TGF-beta receptor signals upstream of CDK. SMAD proteins therefore mediate transcriptional activation or repression depending on their associated partners.

Williams et al. (2006) found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (190020) allele than wildtype cells. Depletion of RB from HRAS-transformed mouse cells or human tumor cells harboring HRAS pathway mutations inhibited their proliferation and anchorage-independent growth. In contrast to Rb -/- mouse fibroblasts, p107 -/- and p130 (RBL2; 180203) -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells. Moreover, loss of RB in human tumor cells harboring an HRAS mutation resulted in increased expression of p107, and overexpression of p107, but not RB, strongly inhibited proliferation of these tumor cells. Williams et al. (2006) concluded that RB and p107 have distinct roles in HRAS-mediated transformation and that p107 has a role as a tumor suppressor in the context of activated HRAS.

Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E (see CCNE1; 123837)-CDK2 pathway, including Cdkn1a (116899), Rb1, Rbl1, Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.


Gene Structure

Ichimura et al. (2000) determined that the RBL1 gene contains 22 exons and spans more than 100 kb.


Mapping

Ewen et al. (1991) used a partial cDNA for human p107 to map the gene to 20q11.2 by fluorescence in situ hybridization.

Huppi et al. (1996) found that the mouse Rbl1 gene maps to the distal end of chromosome 2, as does also the E2f1 gene (189971).


Animal Model

LeCouter et al. (1998) introduced a null mutation in p107 into the germ line of mice and bred into a BALB/cJ genetic background. Mice lacking p107 were viable and fertile but displayed impaired growth, reaching about 50% of normal weight by 21 days of age. Mutant mice exhibited a myeloproliferative disorder characterized by ectopic myeloid hyperplasia in the spleen and liver. Embryonic p107 -/- fibroblasts and primary myoblasts isolated from adult p107 -/- mice displayed a striking 2-fold acceleration in doubling time. However, cell sort analysis indicated that the fraction of cells in G1, S, and G2 was unaltered, suggesting that the different phases of the cell cycle in p107 -/- cells was uniformly reduced by a factor of 2. Western analysis of cyclin expression in synchronized p107 -/- fibroblasts revealed that expression of cyclins E and A preceded that of D1. Mutant embryos expressed approximately twice the normal levels of Rb, whereas p130 levels were unaltered. Finally, mutant mice reverted to a wildtype phenotype following a single backcross with C57BL/6J mice, suggesting the existence of modifier genes that have potentially epistatic relationships with p107. LeCouter et al. (1998) concluded that p107 has an important role in negatively regulating the rate of progression of the cell cycle, but in a strain-dependent manner.

To examine the role of p107 in mouse lateral ventricles, Vanderluit et al. (2004) developed p107-null mice. Adult mutant mice had elevated numbers of proliferating progenitor cells in their lateral ventricles. In vitro neurosphere assays revealed an increase in the number of neurosphere-forming cells from p107 -/- brains that exhibited enhanced capacity for self-renewal. An expanded stem cell population in p107-deficient mice was indicated in vivo by increased numbers of slowly cycling cells in the lateral ventricles and accelerated rates of neural precursor repopulation after progenitor ablation. Notch1 (190198) was upregulated in mutant neurospheres in vitro and brains in vivo. Chromatin immunoprecipitation and p107 overexpression suggested that p107 may modulate the Notch1 pathway. Vanderluit et al. (2004) concluded that p107 negatively regulates the number of neural stem cells in developing and adult brain, a function distinct from that of Rb.

Haigis et al. (2006) found that Rb was expressed in all epithelial cells of mouse colon, whereas p107 was expressed predominantly in the lower half of the crypt, and p130 was expressed in the upper portion of the crypt and in the epithelium lining the lumen. Similarly, undifferentiated cells in the mouse small intestinal crypt expressed Rb and p107, whereas differentiated cells in the villi expressed Rb and p130. Conditional deletion of Rb or p130 increased p107 levels, and Rb/p130 double mutants had even higher levels of p107. Although mutating any of these 3 genes singly had little or no effect, loss of Rb and p107 or p130 together produced chronic hyperplasia and dysplasia of the small intestinal and colonic epithelium. In Rb/p130 double mutants, this hyperplasia was associated with defects in terminal differentiation of specific cell types and was dependent on the increased proliferation seen in the epithelium of mutant animals.


REFERENCES

  1. Chen, C.-R., Kang, Y., Siegel, P. M., Massague, J. E2F4/5 and p107 as Smad cofactors linking the TGF-beta receptor to c-myc repression. Cell 110: 19-32, 2002. [PubMed: 12150994] [Full Text: https://doi.org/10.1016/s0092-8674(02)00801-2]

  2. Ewen, M. E., Xing, Y., Lawrence, J. B., Livingston, D. M. Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell 66: 1155-1164, 1991. [PubMed: 1833063] [Full Text: https://doi.org/10.1016/0092-8674(91)90038-z]

  3. Haigis, K., Sage, J., Glickman, J., Shafer, S., Jacks, T. The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium. J. Biol. Chem. 281: 638-647, 2006. [PubMed: 16258171] [Full Text: https://doi.org/10.1074/jbc.M509053200]

  4. Huppi, K., Siwarski, D., Mock, B. A., Dosik, J., Hamel, P. A. Molecular cloning, chromosomal mapping, and expression of the mouse p107 gene. Mammalian Genome 7: 353-355, 1996. [PubMed: 8661722] [Full Text: https://doi.org/10.1007/s003359900102]

  5. Ichimura, K., Hanafusa, H., Takimoto, H., Ohgama, Y., Akagi, T., Shimizu, K. Structure of the human retinoblastoma-related p107 gene and its intragenic deletion in a B-cell lymphoma cell line. Gene 251: 37-43, 2000. [PubMed: 10863094] [Full Text: https://doi.org/10.1016/s0378-1119(00)00193-1]

  6. Kim, K. K., Soonpaa, M. H., Wang, H., Field, L. J. Developmental expression of p107 mRNA and evidence for alternative splicing of the p107 (RBL1) gene product. Genomics 28: 520-529, 1995. [PubMed: 7490090] [Full Text: https://doi.org/10.1006/geno.1995.1184]

  7. LeCouter, J. E., Kablar, B., Hardy, W. R., Ying, C., Megeney, L. A., May, L. L., Rudnicki, M. A. Strain-dependent myeloid hyperplasia, growth deficiency, and accelerated cell cycle in mice lacking the Rb-related p107 gene. Molec. Cell. Biol. 18: 7455-7465, 1998. [PubMed: 9819431] [Full Text: https://doi.org/10.1128/MCB.18.12.7455]

  8. Vanderluit, J. L., Ferguson, K. L., Nikoletopoulou, V., Parker, M., Ruzhynsky, V., Alexson, T., McNamara, S. M., Park, D. S., Rudnicki, M., Slack, R. S. p107 regulates neural precursor cells in the mammalian brain. J. Cell Biol. 166: 853-863, 2004. [PubMed: 15353549] [Full Text: https://doi.org/10.1083/jcb.200403156]

  9. Wang, Y., Baskerville, S., Shenoy, A., Babiarz, J. E., Baehner, L., Blelloch, R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nature Genet. 40: 1478-1483, 2008. [PubMed: 18978791] [Full Text: https://doi.org/10.1038/ng.250]

  10. Williams, J. P., Stewart, T., Li, B., Mulloy, R., Dimova, D., Classon, M. The retinoblastoma protein is required for Ras-induced oncogenic transformation. Molec. Cell. Biol. 26: 1170-1182, 2006. [PubMed: 16449633] [Full Text: https://doi.org/10.1128/MCB.26.4.1170-1182.2006]


Contributors:
Patricia A. Hartz - updated : 2/11/2009
Patricia A. Hartz - updated : 9/19/2007
Patricia A. Hartz - updated : 2/24/2005
Stylianos E. Antonarakis - updated : 7/26/2002
Ada Hamosh - updated : 8/18/2000
Alan F. Scott - updated : 9/27/1995

Creation Date:
Victor A. McKusick : 10/4/1991

Edit History:
carol : 01/10/2022
carol : 06/17/2011
mgross : 2/16/2009
terry : 2/11/2009
mgross : 10/9/2007
terry : 9/19/2007
terry : 9/19/2007
alopez : 8/3/2006
terry : 8/1/2006
mgross : 2/24/2005
mgross : 7/26/2002
mgross : 7/26/2002
alopez : 10/12/2000
terry : 8/18/2000
terry : 6/13/1996
terry : 6/11/1996
terry : 4/17/1996
mark : 3/7/1996
carol : 4/19/1994
supermim : 3/16/1992
carol : 10/4/1991