Mutant forms of the gene encoding the tumor suppressor p53 are found in numerous human malignancies, but the physiologic function of p53 and the effects of mutations on this function are unknown. The p53 protein binds DNA in a sequence-specific manner and thus may regulate gene transcription. Cotransfection experiments showed that wild-type p53 activated the expression of genes adjacent to a p53 DNA binding site. The level of activation correlated with DNA binding in vitro. Oncogenic forms of p53 lost this activity. Moreover, all mutants inhibited the activity of coexpressed wild-type p53, providing a basis for the selection of such mutants during tumorigenesis.

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

Lysosomes, melanosomes and platelet-dense granules are abnormal in the mouse hypopigmentation mutant pearl. The beta3A subunit of the AP-3 adaptor complex, which likely regulates protein trafficking in the trans - Golgi network/endosomal compartments, was identified as a candidate for the pearl gene by a positional/candidate cloning approach. Mutations, including a large internal tandem duplication and a deletion, were identified in two respective pearl alleles and are predicted to abrogate function of the beta3A protein. Significantly lowered expression of altered beta3A transcripts occurred in kidney of both mutant alleles. The several distinct pearl phenotypes suggest novel functions for the AP-3 complex in mammals. These experiments also suggest mutations in AP-3 subunits as a basis for unique forms of human Hermansky-Pudlak syndrome and congenital night blindness, for which the pearl mouse is an appropriate animal model.