Strain-Dependent Myeloid Hyperplasia, Growth Deficiency, and Accelerated Cell Cycle in Mice Lacking the Rb-Related p107 Gene

Abstract

To investigate the function of the Rb-related p107 gene, a null mutation in p107 was introduced 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 diathetic 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 twofold acceleration in doubling time. However, cell sort analysis indicated that the fraction of cells in G 1 , S, and G 2 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 level of Rb, whereas p130 levels were unaltered. Lastly, mutant mice reverted to a wild-type phenotype following a single backcross with C57BL/6J mice, suggesting the existence of modifier genes that have potentially epistatic relationships with p107. Therefore, we conclude that p107 is an important player in negatively regulating the rate of progression of the cell cycle, but in a strain-dependent manner.The Rb family of structurally related nuclear phosphoproteins, consisting of Rb, p107, and p130, is believed to play important roles in regulating cell proliferation and differentiation (42). A central function of the Rb family is to negatively regulate the activity of E2F transcription factors that control the transcription of many cell cycle-regulated genes (41). Cyclin-dependent kinases (cdks) differentially regulate the phosphorylation of Rb, p107, and p130 during the cell cycle. Consequently, different Rb family members are hypophosphorylated during different phases of the cell cycle, allowing the formation of complexes that contain specific E2F transcription factors (10-13, 21, 55).The E2F family of transcription factors is encoded by multiple genes (at least six E2Fs and three DP-type members) and can regulate the transcription of many different genes that are putatively activated or repressed by specific E2F:DP heterodimers (26). Rb family-E2F1-5:DP complexes are believed to bind promoters at E2F sites and inhibit transcription by binding HDAC1, a histone deacetylase, to repress gene expression via chromatin remodeling (8,36,37) or, alternatively, to interfere with functional interactions between transactivation domains and components of the basal transcriptional machinery (9, 53). Thus, different E2F-regulated genes can be either activated or repressed depending on whether E2F:DP or an Rb family-E2F:DP complex is bound. Presumably, it is the cyclic activation and repression of E2F-regulated genes that controls progression through the cell cycle (41, 62).The phenotype of mice carrying targeted mutations in Rb supports the assertion that Rb...

A dynamic switch in Rb+/− mediated neuroendocrine tumorigenesis

“…Loss of p130 results in embryonic lethality and loss of p107 results in myeloid hyperplasia and growth defects specifically on a 129Sv  BALB/c genetic background, phenotypes which are fully rescued by breeding into a C57BL/6 background (Cobrinik et al, 1996;Lee et al, 1996;LeCouter et al, 1998a, b). Additionally, loss of E2f3 results in fully penetrant embryonic lethality on a 129Sv genetic background, whereas many E2f3-deficient animals live to adulthood on a 129Sv  C57BL/6 background (Humbert et al, 2000;Cloud et al, 2002).…”

MYC oncogenes and human neoplastic disease

“…Such animals might be expected to develop a more rapid onset of lymphoma. A further prediction is that cross-bred animals which harbor both a wild-type Ig-c-myc transgene and a homozygous p107 deletion (LeCouter et al, 1998) would show accelerted lymphomagenesis at a rate which mirrored that seen in animals with mutant c-myc transgenes. Important clinical questions include whether translocated c-myc alleles acquire an increasing number of somatic mutations during disease progression and whether particular types of somatic mutations are predictive of clinical course.…”

Cell cycle regulation in hematopoietic stem cells

“…A firm role for Rb family members in the control of HSC quiescence was not established until recently, as considerable functional redundancy exists within this family and as all members are expressed, albeit at different levels, in HSCs (Passegué et al, 2005). For instance, no hematopoietic phenotype was observed in p130-deficient mice (Cobrinik et al, 1996), and p107 deletion resulted in only a mild myeloid hyperplasia (LeCouter et al, 1998). Removal of pRb had also no effect on HSC self-renewal as assessed by serial transplantation (Walkley and Orkin 2006), and although pRb-deficient mice exhibited myeloid expansion, this was shown to be a non-cell autonomous effect (Walkley and Orkin 2006;Walkley et al, 2007).…”