Gene: [11q133/CCND1] cyclin D1; parathyroid adenomatosis 1 (cyclin D1 deficiency); [PRAD1 ]

SUM

 There are several features in that D cyclins differ from the other: all the three cyclin D genes encode a similar small size protein ranging from 289 to 295 amino acid residues, the shortest cyclins found so far. Second, they all lack the so called destruction box identified in the N-terminus of both A- and B-type cyclins, which targets it for ubiquitin-dependent degradation (Glotzer-1991). This suggests either that the D-type cyclins have evolved a different mechanism to govern their periodic degradation during each cell cycle or that they do not undergo such destruction. Third the three human cyclin D genes share very high similarity over their entire coding region, 60% between D1 and D2, 60% between D2 and D3, and 52% between D1 and D3. Fourth members of the D-type cyclins are more closely related to each other than are members of the B-type cyclins, averaging 78% for three cyclin D genes in the cyclin box versus 57% for two cyclin B genes (Xiong-1992)."

FUN

 Cyclin D genes play the roles as effectors of G1 transition and are differentially and redundantly expressed during the G1 phase of the cell cycle."

MOP

 [1] CYCD1 encodes the smallest (34kD) cyclin protein identified so far. By comparison with A-type (GEM:04q/CCNA) and B-type (GEM:05q1/CCNB1) cyclins, the difference is due to the lack of almost the entire N-terminal segment that contains the so called destruction box identified in both A- and B-type cyclins, which targets it for ubiquitin-dependent degradation (Glotzer-1991). This suggests either that the D-type cyclins have evolved a different mechanism to govern their periodic degradation during each cell cycle or that they do not undergo such destruction.
[2] D1 cyclin protein contain PEST sequences, which have been suggested to target proteins for rapid (and constitutive) degradation (Rogers-1986), near the carboxyl terminus (PEST-FIND score +13)."

EXP

 The timing of cyclin D gene expression depends strongly on cell context (Inaba-1992)."

PAT

 [1] Alterations of cyclin D1 may contribute to the pathogenesis of some human tumors. Recent evidence now suggests that CCND1 may represent the target oncogene because it appears to be the first transcriptional unit telomeric to the breakpoint and is deregulated in tumor cells (Withers-1991). Truncated cyclin D1 transcripts have been identified in such tumors (Withers-1991) and in a human glioblastoma (Xiong-1991); these RNAs, which appear to result from differential polyadenylation, lack 3' nontranslated sequences that migth be important in destabilizing CCND1 mRNA. Either the inappropriate expression or the reduced turnover of CCND1 mRNA in such cell might perturb normal cell cycle controls. By analogy, the cyclin D2 (GEM:12p13/CCND2) and D3 (GEM:06p21/CCND3) genes might also be altered in human malignancies. Chromosomal deletions and translocations affecting the chromosome 12p are among the most common rearrangements observed in childhood acute lymphoblastic leukemia (Raimondi-1986), whereas an iso(6p) chromosome is a frequent anomaly in retinoblastoma (Squire-1985; Horsthemke-1989). Although antibodies to the CCND1 and CCND2 proteins immunoprecipitate complexes containing p34-cdc2-like polypeptides, they lack overt histone H1 kinase activity in vitro (Matsushime-1991), suggesting that CCND proteins might be inhibitors of cdc2-like enzymes, might target them to other substrates, or might act as regulators of cdc25 phosphatases (Galaktionov-1991). The retinoblastoma protein (p105-Rb) is an attractive candidate substrate because it normally functions to suppress S-phase entry and is presumed to be inactivated as a result of its phosphorylation by a cdc2-like kinase (Buchkovich-1989; Chen-1989; DeCaprio-1989; Lin-1991). Functional interactions of cyclin D gene products with such proteins could provide a mechanistic explanation for how they might regulate G-1 progression.
[2] Cyclin D1 was found to be translocated adjacent to the parathyroid hormone gene promoter, suggesting that perturbations in its expression might contribute to malignancy (Motokura-1991). A chromosomal inversion that juxtaposes the 5' regulatory elements of the parathyroid hormone promoter located on chromosome 11, band p15, with the complete coding region of CCND1 on 11q13 results in the tumor-specific overexpression of cyclin D1 mRNA (Rosenberg-1991; Motokura-1991).
[3] CCND1 is also contained within an amplicon found in 15-20% of breast carcinomas and squamous cell tumors of the head and neck (Lammie-1991, and references therein).
[4] The amplified region of human chromosome 11 frequently includes genes encoding two fibroblast growth factors(FGFs) (INT2 and HST1) (Adelaide-1988; Yoshida-1988; Varley-1988). CCND1 is usually transcribed in such tumor cells (Rosenberg-1991), whereas oncogenes of the FGF family are usually not (Fantl-1990; Liscia-1989; Theillet-1989). A translocation breakpoint cluster region (BCL1) was identified in centrocytic B cell lymphomas with a t(11;14)(q13;q32) chromosomal translocation that involves the immunoglobulin heavy chain locus on chromosome 14 (Erikson-1984; Tsujimoto-1985; Koduru-1989)."

EAG

 [1] There are three cyl genes (cyl1, cyl2 and cyl3) in the mouse genome. On the basis of the sequence comparison, the cyl1 gene appears to be the mouse homolog of human CCND1, cyl2 - of the CCND2, and cyl3 - of the CCND3 (Xiong-1992).
[2] Murine genes closely related to human cyclin D1 have been identified (Matsushime-1991; Xiong-1991). The amino acid sequence of the predicted murine cyclin D1 protein is virtually identical to its human counterpart, suggesting that individual cyclin D genes are highly conserved between species."

EVO

 [1] The D-type cyclins represent a distinct subfamily. The three cyclin D genes are more closely related to their mammalian counterparts than to one another or to the other subclasses of cyclins such as A, B, C, and E. Phylogenetic analysis shows that on structural grounds cyclin D1 is on a different branch of the evolutionary tree from A-, B-, or CLN-type cyclins.
[2] Members of the D-type cyclins are more closely related to each other than are members of the B-type cyclins, averaging 78% for three cyclin D genes in the cyclin box versus 57% for two cyclin B genes (Xiong-1992). The three human cyclin D genes share very high similarity over their entire coding region, 60% between D1 and D2, 60% between D2 and D3, and 52% between D1 and D3.
[3] Protein coding sequences of the D-cyclins share a similar exon-intron organization, consistent with their origins from a common ancestral gene. Comparison of the genomic clones of cyclins D1, D2, and D3 revealed that the coding regions of all three human CCND genes are interrupted at the same position by an intron (Xiong-1992). This indicated that the intron occured before the separation of cyclin D genes (Xiong-1992).
[4] An extremely high sequence similarity between human CCND1 and mouse cyl1 was found (94% identity over the entire coding region)."

REL

 GEM:11q133/BCL1.

REF

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KEY

 nucm, onc, repr, horm

CLA

 coding, basic

LOC

 11 q13.3

MIM

 MIM: 168461

SYN

 PRAD1

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