Table 4. Comparison of RAR Fusion... | American Society of Hematology

Table 4.

Comparison of RAR Fusion Partner Proteins

	PML	PLZF	NPM	NuMA
Isoforms	Up to 20 splicing products identified5,11-13,157 159	One²⁸⁹	Two major isoforms. A third associates with nuclear matrix420,426,427,579 580	At least three519 520
Secondary structure motifs	N-terminal Pro-rich,¹⁶⁷ RING and B box,163,164,166 coiled coil,163,167,170,171variable acidic C-terminal region157 159	N-terminal BTB/POZ domain; C-terminal kruppel-like Zn fingers289,359 373	Two acidic domains, one metal binding motif, two NLS, ATP-binding site420,426,430-433,440,579 580	Central coiled coil flanked by two globular domains521 522
Homodimer	Through the coiled domain163,170 171	Through the BTB/POZ domain³⁷³	Forms hexamers through N- and C-terminal portion445 446	Through coiled coil domain515 521-523
Heterologous interaction	Through the coiled coil, N-terminal Pro-rich domain, and possibly RING and B box domains163-165 170-172	Through the BTB/POZ domain and the first two Zn fingers216,294 373	Through the acidic domains and C-terminal region433,434,437-439,446,455,456,462,581 582	Through C-terminal domain522 534
Phosphorylation	Ser and Tyr residues, substrate of cyclin A/cdk2 has casein kinase II sites5,170,174,181 182	Ser and Thr residues. Possible cdc2 phosphorylation (Licht et al, unpublished data)	Casein kinase II, nuclear kinase II, PKC and cdc2 kinases469,471 583-587	Cdc2 Kinase, cyclic AMP kinase, PKC, Ca/calmodulin kinase468,469,471 583-585
Nuclear localization	Mainly in nuclear bodies. Also in cytoplasm and other nuclear regions170,173 191	Nuclear speckles, partial overlap with PML216 383	Principally nucleolar, also nucleoplasm. Shuttles to cytoplasm236,447-449,579 580	Interphase—diffuse and speckled511,517,530,537 Mitosis—binds spindle poles517,530-533,535,536 588
Nuclear matrix association	Associates with nuclear matrix182,191,197 201	Possible—through the nuclear bodies	One isoform associates with the matrix420,426,427,579 580	During interphase538 539
Expression pattern	Present in inflammatory tissues183-186 myeloid precursor cells,173,189 induced by IFNs177,188 189	CD34⁺ progenitors macrophages, mouse embryo CNS, liver, heart, kidney, limb and tail buds359,367 387	Ubiquitous⁴²⁰	Ubiquitous, except in some terminally differentiated cells517 589
Cell cycle	Increases in G0 to G1 transition and decreases as cells progress to S phase174,183 184	Blocks cells in G1/S correlating with downregulation of cyclin A403 406	Peaks at onset of S phase—declines as cells enter G2460 590	Phosphorylated in G2/M526,527,591,592 essential for M phase510,511,525,527,531-533 535
Transcription and RNA metabolism	Transcriptional repression and activation. Involved in retinoid receptor signaling. Possible role in translation132,182,212,230,211,215 214	Transcriptional repression394 593	Modulates transcriptional effects of YY1 and IRF-1. Involved in ribosome biogenesis235-237,461 462	Colocalizes and coprecipitates with snRNPs and splicing complexes⁵³⁹
Protein partners	Sentrin, PLZF, Rb, L7 leucine zipper, EF-1, ribosomal P proteins216,220,229 230 and see Table 3	PML, LRF, SMRT, N-Cor, HDAC, sin3a, sin3b, Rb, Cdc2, eto216,294-296,398,401 594-596	Rev, Tat, Rex, nucleolin, p120, YY1. IRF-1433,434,437-439,461,462,581 582	Tubulin and mitotic spindle510,511,525,527,531-533 535
Action on cell growth	Growth suppression in NB4, HeLa and CHO cells blocks transformation in rat embryo fibroblasts and 3T3 cells167,184,210 248-250	Growth suppression differentiation block⁴⁰³	Expression highest in tumor cells, overexpression causes 3T3 cells to transform420,457,458,460,461,467 597-602	Required for proper completion of mitosis510,511,525,527,531-533 535
Apoptosis	Removal delays apoptosis; association with sentrin and targeting by As₂O₃ imply role in apoptosis167,168,172,224 311	Promotes cell survival with factor withdrawal⁴⁰³	Becomes hypophosphorylated and degraded during apoptosis470 471	Specifically targeted for proteolysis by caspases542 544-547
Miscellaneous	Targeted during certain viral infections238,239 241-244	DNA binding site $GT \frac{A}{C} \frac{A}{C} AGT$	Nucleic acid binding237,442,443 450	Attaches to DNA matrix attachment regions (MAR)540 541
Knock out data	K/O mice susceptible to infections, susceptible to transforming agents, lack IFN-induced growth suppression, defective induction of p21 by ATRA132 190	Musculoskeletal-limb defects, impaired spermatogenesis, T-cell lymphopenia³⁸⁸ (P. P. Pandolfi, personal communication)	None published to date	None published to date
Function	Tumor suppressor involved in growth suppression, differentiation, and immune response pathways. Possible role in translation. Transcriptional modulator.	Growth suppressor, transcriptional repressor, control of developmental programs and differentiation, possibly through hox genes.	Ribonucleoprotein maturation and transport, shuttle proteinsbetween cytoplasm and nucleolus. Transcriptional modulator. Implicated in DNA recombination.	Structural role in interphase and in particular mitotic cells. Major target of apoptosis program.

	PML	PLZF	NPM	NuMA
Isoforms	Up to 20 splicing products identified5,11-13,157 159	One²⁸⁹	Two major isoforms. A third associates with nuclear matrix420,426,427,579 580	At least three519 520
Secondary structure motifs	N-terminal Pro-rich,¹⁶⁷ RING and B box,163,164,166 coiled coil,163,167,170,171variable acidic C-terminal region157 159	N-terminal BTB/POZ domain; C-terminal kruppel-like Zn fingers289,359 373	Two acidic domains, one metal binding motif, two NLS, ATP-binding site420,426,430-433,440,579 580	Central coiled coil flanked by two globular domains521 522
Homodimer	Through the coiled domain163,170 171	Through the BTB/POZ domain³⁷³	Forms hexamers through N- and C-terminal portion445 446	Through coiled coil domain515 521-523
Heterologous interaction	Through the coiled coil, N-terminal Pro-rich domain, and possibly RING and B box domains163-165 170-172	Through the BTB/POZ domain and the first two Zn fingers216,294 373	Through the acidic domains and C-terminal region433,434,437-439,446,455,456,462,581 582	Through C-terminal domain522 534
Phosphorylation	Ser and Tyr residues, substrate of cyclin A/cdk2 has casein kinase II sites5,170,174,181 182	Ser and Thr residues. Possible cdc2 phosphorylation (Licht et al, unpublished data)	Casein kinase II, nuclear kinase II, PKC and cdc2 kinases469,471 583-587	Cdc2 Kinase, cyclic AMP kinase, PKC, Ca/calmodulin kinase468,469,471 583-585
Nuclear localization	Mainly in nuclear bodies. Also in cytoplasm and other nuclear regions170,173 191	Nuclear speckles, partial overlap with PML216 383	Principally nucleolar, also nucleoplasm. Shuttles to cytoplasm236,447-449,579 580	Interphase—diffuse and speckled511,517,530,537 Mitosis—binds spindle poles517,530-533,535,536 588
Nuclear matrix association	Associates with nuclear matrix182,191,197 201	Possible—through the nuclear bodies	One isoform associates with the matrix420,426,427,579 580	During interphase538 539
Expression pattern	Present in inflammatory tissues183-186 myeloid precursor cells,173,189 induced by IFNs177,188 189	CD34⁺ progenitors macrophages, mouse embryo CNS, liver, heart, kidney, limb and tail buds359,367 387	Ubiquitous⁴²⁰	Ubiquitous, except in some terminally differentiated cells517 589
Cell cycle	Increases in G0 to G1 transition and decreases as cells progress to S phase174,183 184	Blocks cells in G1/S correlating with downregulation of cyclin A403 406	Peaks at onset of S phase—declines as cells enter G2460 590	Phosphorylated in G2/M526,527,591,592 essential for M phase510,511,525,527,531-533 535
Transcription and RNA metabolism	Transcriptional repression and activation. Involved in retinoid receptor signaling. Possible role in translation132,182,212,230,211,215 214	Transcriptional repression394 593	Modulates transcriptional effects of YY1 and IRF-1. Involved in ribosome biogenesis235-237,461 462	Colocalizes and coprecipitates with snRNPs and splicing complexes⁵³⁹
Protein partners	Sentrin, PLZF, Rb, L7 leucine zipper, EF-1, ribosomal P proteins216,220,229 230 and see Table 3	PML, LRF, SMRT, N-Cor, HDAC, sin3a, sin3b, Rb, Cdc2, eto216,294-296,398,401 594-596	Rev, Tat, Rex, nucleolin, p120, YY1. IRF-1433,434,437-439,461,462,581 582	Tubulin and mitotic spindle510,511,525,527,531-533 535
Action on cell growth	Growth suppression in NB4, HeLa and CHO cells blocks transformation in rat embryo fibroblasts and 3T3 cells167,184,210 248-250	Growth suppression differentiation block⁴⁰³	Expression highest in tumor cells, overexpression causes 3T3 cells to transform420,457,458,460,461,467 597-602	Required for proper completion of mitosis510,511,525,527,531-533 535
Apoptosis	Removal delays apoptosis; association with sentrin and targeting by As₂O₃ imply role in apoptosis167,168,172,224 311	Promotes cell survival with factor withdrawal⁴⁰³	Becomes hypophosphorylated and degraded during apoptosis470 471	Specifically targeted for proteolysis by caspases542 544-547
Miscellaneous	Targeted during certain viral infections238,239 241-244	DNA binding site $GT \frac{A}{C} \frac{A}{C} AGT$	Nucleic acid binding237,442,443 450	Attaches to DNA matrix attachment regions (MAR)540 541
Knock out data	K/O mice susceptible to infections, susceptible to transforming agents, lack IFN-induced growth suppression, defective induction of p21 by ATRA132 190	Musculoskeletal-limb defects, impaired spermatogenesis, T-cell lymphopenia³⁸⁸ (P. P. Pandolfi, personal communication)	None published to date	None published to date
Function	Tumor suppressor involved in growth suppression, differentiation, and immune response pathways. Possible role in translation. Transcriptional modulator.	Growth suppressor, transcriptional repressor, control of developmental programs and differentiation, possibly through hox genes.	Ribonucleoprotein maturation and transport, shuttle proteinsbetween cytoplasm and nucleolus. Transcriptional modulator. Implicated in DNA recombination.	Structural role in interphase and in particular mitotic cells. Major target of apoptosis program.