But while Kantakouzenos was conducting military operations in Thrace in July 1341, in Constantinople an opposition group formed by the Patriarch John Kalekas, the queen mother, Anna of Savoy, and the megas doux, Alexios Apokaukos, set itself up as the official regency. Moreover, taking advantage of the absence of Kantakouzenos, they stripped him of his offices and confiscated his property.
Nonetheless, in October 1341, John Kantakouzenos was proclaimed Emperor in Didymoteichon, although he maintained that he was joint Emperor with John V and not his rival. The regency responded by crowning the young John V Emperor on 19 November 1341.
When John VI came to power, the Empire was so weakened by the internal conflicts that it was in no position to undertake any military operations. The new emperor, therefore, initiated a policy of intense diplomatic action. He endeavoured to strengthen Byzantine influence in Russia and the Empire of Trebizond, while he also continued to maintain friendly relations with the Mamluks of Egypt.
Kantakouzenos' main concern was the Serbian expansion in Macedonia. Stefan Dusan, who had been crowned emperor in April 1346, completed his conquest of Epiros in 1348 and subdued Thessaly at the same time. He thus established a state which extended, roughly, from the Danube to the Gulf of Corinth and from the Adriatic to the river Nestos in eastern Macedonia. In essence, only Thessalonike and Constantinople remained to be conquered. Dusan needed a fleet to take the Constantinople but Venice, which Dusan approached for assistance, was in no way disposed to replace the Byzantine Empire with a powerful Serbian one. Dusan's efforts therefore remained fruitless. John VI undertook two military operations against the Serbs, in 1348 and in 1350, which, however, scored only a few minor successes.
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The negotiated peace of John VI with the Genoese in 1352 at the end of the Genoese-Venetian war, prompted the Venetians to act in league with John V against the former. John V was then in Thessalonike, and felt particularly resentful at his having been removed from the throne. The Venetians and the Serbs urged him to rebel against Kantakouzenos. Negotiations with the latter were at first successful in averting a civil war, but when, in the summer of 1352, John V, backed by Venetian funds, invaded territory governed by Kantakouzenos's son, Matthew, in Adrianople, war broke out. The deceitful behaviour of John V offered John VI an excuse to depose him formally and definitively following his successful intervention in Adrianople. He ordered that his name be omitted from acclamations and, in 1354, appointed his son, Matthew, joint Emperor.
The wife of Emperor John VI Kantakouzenos, was Irene of Bulgaria, who played an important role during the ensuing wars. She was was placed in charge of the garrison at Didymoteichon during the civil war of 1341-47, and in 1348 she took responsibility for the defense of Constantinople during her husband's absence.
The Kantakouzenos dynasty, however, did not retain its ascendancy long. The popularity of John VI began to wane when his Turkish allies, whom, several years before, he himself had summoned from Asia Minor to assist him in his struggle, established themselves permanently on European soil. In 1352 they had already seized the fortress of Djimbi, near Kallipolis, while in March 1354, after a tremendous earthquake that drove the Byzantine inhabitants away from the area, Orhan's son, Suleiman, occcupied Kallipolis itself. In spite of Kantakouzenos' pleas, the Turks refused to leave the city. The occupation of Kallipolis caused panic among the population of Constantinople, who felt that the capital was now under serious threat. Thus, when John V, who was in Tenedos at the time, entered Constantinople with the support of the Genoese adventurer, Francesco I Gattilusio, the people went over to his side. Kantakouzenos was forced to resign and John V was left in sole possession of the throne.
As for Kantakouzenos, he adopted the monk's habit and thenceforth became monk Joasaph, devoting some yearsof his life to the writing of his famous Histories. Nonetheless, he never ceased to intervene in public affairs until his death, in 1383.